Processes for preparing ASK1 inhibitors

ABSTRACT

The present disclosure provides processes for the preparation of a compound of formula: 
                         
which exhibits apoptosis signal-regulating kinase (“ASK1”) inhibitory activity and is thus useful in the treatment of diseases such as kidney disease, diabetic nephropathy and kidney fibrosis. The disclosure also provides compounds that are synthetic intermediates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under of 35 U.S.C. §119(e) of U.S.Provisional Application 62/096,391, filed on Dec. 23, 2014, and U.S.Provisional Application 62/269,064, filed on Dec. 17, 2015, both ofwhich are hereby incorporated by reference.

FIELD

The present disclosure relates generally to the field of organicsynthetic methodology for the preparation of compounds for the treatmentof apoptosis signal-regulating kinase 1 (“ASK1”) mediated diseases andthe synthetic intermediates prepared thereby.

BACKGROUND

Therapeutic agents that function as inhibitors of ASK1 signaling havethe potential to remedy or improve the lives of patients in need oftreatment for diseases or conditions such as neurodegenerative,cardiovascular, inflammatory, autoimmune, and metabolic disorders. Inparticular, ASK1 inhibitors have the potential to treat cardio-renaldiseases, including kidney disease, diabetic kidney disease, chronickidney disease, fibrotic diseases (including lung and kidney fibrosis),respiratory diseases (including pulmonary arterial hypertension (PAH),chronic obstructive pulmonary disease (COPD) and acute lung injury),acute and chronic liver diseases. There is a need for improved oralternate processes to prepare compounds that are potent and exhibitimproved pharmacokinetic and/or pharmacodynamic profiles for thetreatment of diseases related to ASK1 activation.

SUMMARY

5-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide,also known as5-((4-cyclopropyl-1H-imdazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazole-3-yl)pyridine-2-yl)-4-methylbenzamide(Compound of formula (A)), has the formula:

This compound has been shown to exhibit ASK-1 inhibitory activity (U.S.Pat. No. 8,742,126, which is hereby incorporated by reference in itsentirety). The present disclosure provides processes for making acompound of formula (A) or a salt or solvate thereof.

In one embodiment, provided is a process for preparing a compound offormula (A), salt thereof, or solvate thereof:

comprising the steps of:

(a) carboxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate or salt thereof:

(b) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(c) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In another embodiment, provided is a process for preparing a compound offormula (A) or salt or solvate thereof:

comprising the steps of:

(a) cyclizing a compound of formula (F):

under reaction conditions sufficient to form a compound of formula (E)or a salt thereof:

(b) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(c) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(d) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In another embodiment, provided is a process for preparing a compound offormula (A) or salt or solvate thereof:

comprising the steps of:

(a) formylating a compound of formula (G):

under reaction conditions sufficient to form a compound of formula (F):

(b) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(c) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or a salt thereof:

(d) chlorinating a compound of formula (D) or a hydrate, solvate or asalt thereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(e) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In another embodiment, provided is a process for preparing a compound offormula (A) or a salt or solvate thereof:

(a) contacting a compound of formula (H):

with a compound of formula (I):

under reaction conditions sufficient to form a compound of formula (G):

(b) formylating a compound of formula (G) under reaction conditionssufficient to form a compound of formula (F):

(c) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(d) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(e) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(f) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In another embodiment, provided is a process for preparing a compound offormula (A) or a salt or solvate thereof:

(a) tosyloxylating a compound of formula (J):

under reaction conditions sufficient to form a compound of formula (H):

(b) contacting a compound of formula (H) with a compound of formula (I):

under reaction conditions sufficient to form a compound of formula (G):

(c) formylating a compound of formula (G) under reaction conditionssufficient to form a compound of formula (F):

(d) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(e) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(f) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(g) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In another embodiment, provided is a process for preparing a compound offormula (A) or a salt or solvate thereof:

(a) contacting a compound of formula (K) or a salt thereof:

with a compound of formula (L):

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate or salt thereof:

(b) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(c) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).wherein Z is a leaving group.

In another embodiment, provided is a process for preparing a compound offormula (D) or a hydrate, solvate or salt thereof:

comprising the steps of:

(a) carboalkoxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (Q):

and

(b) hydrolyzing a compound of formula (Q) under reaction conditionssufficient to form a compound of formula (D) or a hydrate, solvate orsalt thereof.

In another embodiment, provided is a process for preparing a compound offormula (A) or salt or solvate thereof:

comprising the steps of:

(a) contacting a compound of formula (E) or a salt thereof:

with a compound of formula (C) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (A).

In one embodiment, provided is a process for preparing a compound offormula (A), salt thereof, or solvate thereof:

comprising the steps of:

(a) carboxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate or salt thereof:

(b) contacting a compound of formula (D) or a hydrate, solvate or saltthereof with propylphosphonic anhydride under reaction conditionssufficient to form a compound of formula (R):

and

(c) contacting a compound of formula (R) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acidhydrochloride (Compound of formula (D-a) Form I) characterized by anX-ray powder diffractogram comprising the following peaks: 7.3, 22.3,23.4, 23.9, and 26.8 °2θ±0.2 °2θ, as determined on a diffractometerusing Cu—Kα radiation at a wavelength of 1.5406 Å.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acidhydrochloride (Compound of formula (D-a) Form II) characterized by anX-ray powder diffractogram comprising the following peaks: 8.7, 12.1,25.7, and 26.3 °2θ±0.2°2θ, as determined on a diffractometer using Cu—Kαradiation at a wavelength of 1.5406 Å.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid hydrate(Compound of formula (D) hydrate Form I) characterized by an X-raypowder diffractogram comprising the following peaks: 9.5, 20.4, 24.3,26.5, and 28.7 °2θ±0.2 °2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.5406 Å.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form I) characterized by an X-ray powder diffractogramcomprising the following peaks: 8.7, 15.2, 21.5, and 23.8 °2θ±0.2 °2θ,as determined on a diffractometer using Cu—Kα radiation at a wavelengthof 1.5406 Å.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form II) characterized by a calculated X-ray powderdiffractogram comprising the following peaks: 8.4, 13.6, and 15.5°2θ±0.2 °2θ, as determined on a diffractometer using Cu—Kα radiation ata wavelength of 1.5406 Å.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form III) characterized by an X-ray powder diffractogramcomprising the following peaks: 10.3, 17.1, 18.0, and 25.7 °2θ±0.2 °2θ,as determined on a diffractometer using Cu—Kα radiation at a wavelengthof 1.5406 Å.

The inventions of this disclosure are described throughout. In addition,specific embodiments of the invention are as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) of Compound of formula(D-a) Form I.

FIG. 2 shows a differential scanning calorimeter (DSC) curve of Compoundof formula (D-a) Form I.

FIG. 3 shows a thermogravimetric analysis (TGA) of Compound of formula(D-a) Form I.

FIG. 4 shows an X-ray powder diffraction (XRPD) of Compound of formula(D-a) Form II.

FIG. 5 shows a differential scanning calorimeter (DSC) curve of Compoundof formula (D-a) Form II.

FIG. 6 shows a thermogravimetric analysis (TGA) of Compound of formula(D-a) Form II.

FIG. 7 shows an X-ray powder diffraction (XRPD) of Compound of formula(D) hydrate Form I.

FIG. 8 shows a differential scanning calorimeter (DSC) curve of Compoundof formula (D) hydrate Form I.

FIG. 9 shows a thermogravimetric analysis (TGA) of Compound of formula(D) hydrate Form I.

FIG. 10 shows an X-ray powder diffraction (XRPD) of Compound of formula(D) Form I.

FIG. 11 shows a differential scanning calorimeter (DSC) curve ofCompound of formula (D) Form I.

FIG. 12 shows a thermogravimetric analysis (TGA) of Compound of formula(D) Form I.

FIG. 13 shows an X-ray powder diffraction (XRPD) of Compound of formula(D) Form III.

FIG. 14 shows a differential scanning calorimeter (DSC) curve ofCompound of formula (D) Form III.

FIG. 15 shows a thermogravimetric analysis (TGA) of Compound of formula(D) Form III.

FIG. 16 shows a thermogravimetric analysis (TGA) of Compound of formula(D) Form II and Compound of formula (D) Form I.

FIG. 17 shows a differential scanning calorimeter (DSC) curve ofCompound of formula (D) Form II and Compound of formula (D) Form I.

FIG. 18 shows an X-ray powder diffraction (XRPD) of Compound of formula(D) Form II and Compound of formula (D) Form I.

DETAILED DESCRIPTION Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl,        —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,        —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,        —S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2 or 3 substituents        chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and        —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and        n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. The term “substituted cycloalkyl”also includes cycloalkyl groups wherein one or more of the annularcarbon atoms of the cycloalkyl group has an oxo group bonded thereto. Inaddition, a substituent on the cycloalkyl or cycloalkenyl may beattached to the same carbon atom as, or is geminal to, the attachment ofthe substituted cycloalkyl or cycloalkenyl to the 6,7-ring system.Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1, 2 or 3 substituents chosen fromalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In some embodiments, the heterocyclyl,”“heterocycle,” or “heterocyclic” group is linked to the remainder of themolecule through one of the heteroatoms within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. In addition, a substituent on theheterocyclic group may be attached to the same carbon atom as, or isgeminal to, the attachment of the substituted heterocyclic group to the6,7-ring system. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examplesof heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)— heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridylor furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazoleor benzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “benzyl” refers to the group —CH₂—C₆H₅.

The term “amino” refers to the group —NH₂.

The term “amine” refers to substituted amino, alkyl amine, dialkylamine,or trialkyl amine groups.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “nitro” refers to a group —NO₂.

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” refers to the group —C(O)OR, where R is alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl, which may be optionallyfurther substituted by alkyl, alkoxy, halogen, CF₃, amino, substitutedamino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)C(O)NRR,wherein R^(c) is hydrogen or alkyl and each R is hydrogen, alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthio” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxy” or “hydroxyl” refers to the group —OH.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

A “leaving group” includes a molecular fragment that can depart with apair of electrons from a covalent bond to the reacting carbon atomduring a chemical reaction.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given formula is intended to encompass the compounds ofthe disclosure, and the pharmaceutically acceptable salts,pharmaceutically acceptable esters, isomers, tautomers, solvates,isotopes, hydrates, polymorphs, and prodrugs of such compounds.Additionally, the compounds of the disclosure may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given formula depends upon the numberof asymmetric centers present (there are 2^(n) stereoisomers possiblewhere n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis orby resolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present disclosure, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as “tautomeric isomers” or “tautomers.”Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.Non-limiting examples of amide-comprising and imidic acid-comprisingtautomers are shown below:

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “solvate” refers to a complex formed by the combining of acompound and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound and water.

The term “prodrug” refers to compounds that include chemical groupswhich, in vivo, can be converted and/or can be split off from theremainder of the molecule to provide for the active drug, apharmaceutically acceptable salt thereof or a biologically activemetabolite thereof.

Any formula or structure given herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes compounds in which from 1 to n hydrogensattached to a carbon atom is/are replaced by deuterium, in which n isthe number of hydrogens in the molecule. Such compounds exhibitincreased resistance to metabolism and are thus useful for increasingthe half life of any compound of Formula I when administered to amammal. See, for example, Foster, “Deuterium Isotope Effects in Studiesof Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Suchcompounds are synthesized by means well known in the art, for example byemploying starting materials in which one or more hydrogens have beenreplaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base “salts” by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. In some cases, the “salt” ofa given compound is a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” of a given compound refers to saltsthat retain the biological effectiveness and properties of the givencompound, and which are not biologically or otherwise undesirable.

Base addition salts can be prepared from inorganic and organic bases.Salts derived from inorganic bases include, by way of example only,sodium, potassium, lithium, ammonium, calcium and magnesium salts. Saltsderived from organic bases include, but are not limited to, salts ofprimary, secondary and tertiary amines, such as alkyl amines, dialkylamines, trialkyl amines, substituted alkyl amines, di(substituted alkyl)amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl)amines, tri(substituted alkenyl) amines, cycloalkyl amines,di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkylamines, disubstituted cycloalkyl amine, trisubstituted cycloalkylamines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amines, disubstituted cycloalkenylamine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclicamines, mixed di- and tri-amines where at least two of the substituentson the amine are different and are selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heteroaryl, heterocyclic, and the like. Also included are amines wherethe two or three substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group. Amines are of general structureN(R³⁰)(R³¹)(R³²), wherein mono-substituted amines have 2 of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substitutedamines have 1 of the three substituents on nitrogen (R³⁰, R³¹ and R³²)as hydrogen, whereas tri-substituted amines have none of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ andR³² are selected from a variety of substituents such as hydrogen,optionally substituted alkyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocyclyl and the like. The above-mentioned aminesrefer to the compounds wherein either one, two or three substituents onthe nitrogen are as listed in the name. For example, the term“cycloalkenyl amine” refers to cycloalkenyl-NH₂, wherein “cycloalkenyl”is as defined herein. The term “diheteroarylamine” refers toNH(heteroaryl)₂, wherein “heteroaryl” is as defined herein and so on.Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike. Acid addition salts may be prepared from inorganic and organicacids. Salts derived from inorganic acids include hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Salts derived from organic acids include acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and thelike.

The term “reaction conditions” is intended to refer to the physicaland/or environmental conditions under which a chemical reactionproceeds. The term “under conditions sufficient to” or “under reactionconditions sufficient to” is intended to refer to the reactionconditions under which the desired chemical reaction can proceed.Examples of reaction conditions include, but are not limited to, one ormore of following: reaction temperature, solvent, pH, pressure, reactiontime, mole ratio of reactants, the presence of a base or acid, orcatalyst, radiation, etc. Reaction conditions may be named after theparticular chemical reaction in which the conditions are employed, suchas, coupling conditions, hydrogenation conditions, acylation conditions,reduction conditions, etc. Reaction conditions for most reactions aregenerally known to those skilled in the art or can be readily obtainedfrom the literature. Exemplary reaction conditions sufficient forperforming the chemical transformations provided herein can be foundthroughout, and in particular, the examples below. It is alsocontemplated that the reaction conditions can include reagents inaddition to those listed in the specific reaction.

The term “reagent” refers to a substance or compound that can be addedto bring about a chemical reaction.

The term “chlorinating reagent” refers to a compound that can be addedto carry out a chlorination reaction.

The term “ammonium reagent” refers to an ammonium compound, includingbut not limited to ammonium acetate, ammonium formate, or ammoniumhydroxide.

The term “copper reagent” refers to a copper compound, including but notlimited to Cu(OAc)₂, Cu(OTf)₂, Cu₂O, and CuBr.

The term “additive” can refer to a compound that can be added to achemical reaction.

The term “coupling reagent” or “coupling agent” refers to a compoundthat aids in bringing about a reaction to couple one compound to anothercompound.

The terms “organolithium reagent” or “organolithium base” refer to anorganometallic compound that contains a carbon-lithium bond.

The term “Grignard reagent” refers to a compound having magnesium withan organic radical and a halogen.

The term “ligand” refers to ion or molecule that binds to a centralmetal atom to form a coordination complex.

The term “organic base” is an organic compound that acts as a base.

The term “organic acid” is an organic compound that acts as an acid.

The term “catalyst” refers to a chemical substance that enables achemical reaction to proceed at a usually faster rate or under differentconditions (such as at a lower temperature) than otherwise possible.

The term “co-catalyst” refers to a chemical substance that improvescatalytic activity.

As used herein, the term “about” used in the context of quantitativemeasurements means the indicated amount ±10%, or alternatively theindicated amount ±5% or ±1%.

In addition, abbreviations as used herein have respective meanings asfollows:

° C. Degree Celsius 2-MeTHF 2-methyltetrahydrofuran Ac Acetate Ac₂OAcetic anhydride Ad 1-adamantyl a-phos Aromatic amide-derived phosphineaq. Aqueous ASK1 Apoptosis signal-regulating kinase 1 Bu ButylCyJohnPhos (2-Biphenyl)dicyclohexylphosphine d Doublet dbadibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCMDichloromethane DMAc N,N-dimethylacetamide DMAP 4-DimethylaminopyridineDMF Dimethylformamide DMF-DPA Dimethyl formamide di-n-propyl acetal DMSODimethylsulfoxide Dpcb diphosphinidenecyclobutenes Dppb1,4-Bis(diphenylphosphino)butane Dppe 1,2-Bis(diphenylphosphino)ethaneDppf 1,1′-Bis(diphenylphosphino)ferrocene Dppp1,3-Bis(diphenylphosphino)propane DSC Differential scanning calorimetryDVS Dynamic vapor sorption EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Equiv/eq. Equivalents Et Ethyl EtOAcEthyl acetate g Gram H or hr(s) Hour(s) HOBt Hydroxybenzotriazole HPLCHigh-pressure liquid chromatography Hz Hertz IPA Isopropanol IPAc/iPrOAcIsopropyl acetate iPr/i-Pr Isopropyl J Coupling constant JohnPhos(2-Biphenyl)di-tert-butylphosphine KF Karl Fischer titration Koser'sReagent Hydroxy(tosyloxy)iodobenzene kV Kilovolts L Liter LRMS Lowresolution mass spectrometry m Multiplet M Molar mA Milliamps Me MethylMg or mg Milligram MHz Mega hertz min Minutes mL Milliliter Mmol or mmolMillimole MTBE Methyl-tert-butyl ether NIS N-iodosuccinimide NMPN-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance n-Pr/i-Pr N-propylOTf Triflate PdCl₂(AmPhos)₂ Bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) Ph Phenyl Pr Propyl psig Pound-force persquare inch rac-BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene RT Room temperature S Singlet Sep Septet T Triplet T3P ®Propylphosphonic Anhydride t-Bu tert-Butyl TFA Trifluoroacetic acid TGAThermogravimetric analysis THF Tetrahydrofuran TMEDAN,N,N′,N′-Tetramethylethylenediamine Ts Tosyl V or vol or vols Volumes(mL/g) Wt Weight Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XRPD X-ray powder diffraction Δ Chemical shift μLMicroliterProcesses

The present processes may be performed using methods disclosed hereinand routine modifications thereof which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein, e.g.compounds having structures described by one or more of Formula A, B, C,D, D-a, E, F, G, H, I, J, K, L, L-a, L-b, M, N, N-a, O, P, P-a, P-b, Q,R, or other formulas or compounds disclosed herein (e.g. numberedcompounds 2-1, 2-2, etc.), may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g. from Sigma Aldrich or other chemical suppliers.

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3)283-302). Racemic mixtures of chiral compounds of the disclosure can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994). Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched substrate. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

As described generally above, the disclosure provides in someembodiments processes for making a compound of formula (A).

Scheme 1 represents an exemplary synthesis of a compound of formula (A)and can be carried out according to the embodiments described herein. Itis contemplated that the exemplary synthesis shown in Scheme 1 may beparticularly advantageous. For example, the synthesis employs less toxicstarting materials (i.e., using Compound (H) in place of itscorresponding analog having bromide at the tosylate position), avoidstoxic reagents (i.e., CuCN), and employs less toxic solvents (i.e.,using dichloromethane instead of dichloroethane), including at the finalstep of the synthesis. The synthesis also can utilize milder reactionconditions (i.e., avoids high temperatures needed for cyanation, etc.),can avoid the use of heavy metals, and can require less purificationsteps (e.g. avoid column chromatography). The particular reactionconditions and reagents employed in Scheme 1 are discussed below.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) carboxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate, or salt thereof:

(b) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(c) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (B) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate. In someembodiments, a compound of formula (C) may be a trifluoroacetate salt.

In certain embodiments, the reaction conditions of step (a) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, i-PrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (a) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (b) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (b) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

In some embodiments, the reaction conditions of step (b) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (b) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (c) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofurantoluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (c) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(c) comprise a temperature of about 15° C. to about 25° C.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) cyclizing a compound of formula (F):

under reaction conditions sufficient to form a compound of formula (E)or a salt thereof:

(b) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(c) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(d) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (B) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate. In someembodiments, a compound of formula (C) may be a trifluoroacetate salt.

In certain embodiments, the reaction conditions of step (a) comprise anammonium reagent. The ammonium reagent may be ammonium acetate, ammoniumformate, or ammonium hydroxide. In some embodiments, the reactionconditions of step (a) comprise a solvent selected from the groupconsisting of acetic acid, toluene, benzene, and isopropanol. In someembodiments, the reaction conditions of step (a) comprise a temperatureof about 80° C. to about 120° C. In some embodiments, the reactionconditions of step (a) comprise a temperature of about 110° C. to about115° C.

In certain embodiments, the reaction conditions of step (b) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, iPrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (b) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (c) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (c) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

In some embodiments, the reaction conditions of step (c) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (c) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (d) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (d) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofurantoluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (d) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(d) comprise a temperature of about 15° C. to about 25° C.

In one embodiment, the present disclosure provides a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) formylating a compound of formula (G):

under reaction conditions sufficient to form a compound of formula (F):

(b) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(c) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(d) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(e) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (B) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate. In someembodiments, a compound of formula (C) may be a trifluoroacetate salt.

In certain embodiments, the reaction conditions of step (a) comprise areagent selected from the group consisting of acetic anhydride andformic acid, acetic acid monoanhydride and carbonic acid, andtrifluoroacetic acid anhydride and formic acid.

In some embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of dichloromethane,chloroform, acetonitrile, isopropyl acetate, and tetrahydrofuran. Insome embodiments, the reaction conditions of step (a) comprise atemperature of about −10° C. to about 40° C. In some embodiments, thereaction conditions of step (a) comprise a temperature of about 0° C. toabout 5° C.

In certain embodiments, the reaction conditions of step (b) comprise anammonium reagent. The ammonium reagent may be ammonium acetate, ammoniumformate, or ammonium hydroxide. In some embodiments, the reactionconditions of step (b) comprise a solvent selected from the groupconsisting of acetic acid, toluene, benzene, and isopropanol. In someembodiments, the reaction conditions of step (b) comprise a temperatureof about 80° C. to about 120° C. In some embodiments, the reactionconditions of step (b) comprise a temperature of about 110° C. to about115° C.

In certain embodiments, the reaction conditions of step (c) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, iPrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (c) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (d) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (d) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (d) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

In some embodiments, the reaction conditions of step (d) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (d) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (e) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (e) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofurantoluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (e) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(e) comprise a temperature of about 15° C. to about 25° C.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) contacting a compound of formula (H):

with a compound of formula (I):

under reaction conditions sufficient to form a compound of formula (G):

(b) formylating a compound of formula (G) under reaction conditionssufficient to form a compound of formula (F):

(c) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(d) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(e) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(f) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (B) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate. In someembodiments, a compound of formula (C) may be a trifluoroacetate salt.

In certain embodiments, the reaction conditions of step (a) comprise abase. The base may be an organic base (e.g., N,N-diisopropylethylamine,DBU and DMAP), an alkali metal base (e.g., NaH), a hexamethyldisilazanebase (e.g, sodium, potassium and lithium hexamethyldisilazide), acarbonate base (e.g., Cs₂CO₃, Na₂CO₃), or a tert-butoxide (e.g., lithiumtert-butoxide, sodium tert-butoxide, potassium tert-butoxide, ormagnesium di-tert-butoxide). In some embodiments, the base may beN,N-diisopropylethylamine.

In some embodiments, the reaction conditions of step (a) the reactionconditions of step (a) comprise a solvent selected from the groupconsisting of toluene, tetrahydrofuran, 2-methyltetrahydrofuran,methyl-tert-butyl ether, acetonitrile, dioxane, benzene,dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone. Insome embodiments, the reaction conditions of step (a) comprise atemperature of about −78° C. to about 100° C. In some embodiments, thereaction conditions of step (a) comprise a temperature of about 90° C.to about 100° C.

In certain embodiments, the reaction conditions of step (b) comprise areagent selected from the group consisting of acetic anhydride andformic acid, acetic acid anhydride and carbonic acid, andtrifluoroacetic acid anhydride and formic acid.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane,chloroform, acetonitrile, isopropyl acetate, and tetrahydrofuran. Insome embodiments, the reaction conditions of step (b) comprise atemperature of about −10° C. to about 40° C. In some embodiments, thereaction conditions of step (b) comprise a temperature of about 0° C. toabout 5° C.

In certain embodiments, the reaction conditions of step (c) comprise anammonium reagent. The ammonium reagent may be ammonium acetate, ammoniumformate, or ammonium hydroxide. In some embodiments, the reactionconditions of step (c) comprise a solvent selected from the groupconsisting of acetic acid, toluene, benzene, and isopropanol. In someembodiments, the reaction conditions of step (c) comprise a temperatureof about 80° C. to about 120° C. In some embodiments, the reactionconditions of step (c) comprise a temperature of about 110° C. to about115° C.

In certain embodiments, the reaction conditions of step (d) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, i-PrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (d) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (d) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (e) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (e) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (e) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

In some embodiments, the reaction conditions of step (e) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (e) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (f) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (f) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofurantoluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (f) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(f) comprise a temperature of about 15° C. to about 25° C.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) tosyloxylating a compound of formula (J):

under reaction conditions sufficient to form a compound of formula (H):

(b) contacting a compound of formula (H) with a compound of formula (I):

under reaction conditions sufficient to form a compound of formula (G):

(c) formylating a compound of formula (G) under reaction conditionssufficient to form a compound of formula (F):

(d) cyclizing a compound of formula (F) under reaction conditionssufficient to form a compound of formula (E) or a salt thereof:

(e) carboxylating a compound of formula (E) or a salt thereof underreaction conditions sufficient to form a compound of formula (D) or ahydrate, solvate or salt thereof:

(f) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(g) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (B) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate. In someembodiments, a compound of formula (C) may be a trifluoroacetate salt.

In certain embodiments, the reaction conditions of step (a) compriseadding Koser's reagent. In some embodiments, the reaction conditions ofstep (a) comprise a reagent selected from the group consisting of(diacetoxyiodo)benzene organosulfonic acid, (diacetoxyiodo)benzene andp-toluenesulfonic acid, iodosylbenzene/p-toluenesulfonic acid,m-chloroperbenzoic acid/p-toluenesulfonic acid, poly(4-hydroxytosyloxyiodo)styrenes, N-methyl-O-tosylhydroxylamine, Dess-Martinperiodinane/p-toluenesulfonic acid, HIO₃/p-toluenesulfonic acid, ando-iodoxybenzoic acid/p-toluenesulfonic acid.

In some embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of acetonitrile, toluene,benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, andchloroform. In some embodiments, the reaction conditions of step (a)comprise a temperature of about 20° C. to about 100° C. In someembodiments, the reaction conditions of step (a) comprise a temperatureof about 75° C. to about 80° C.

In certain embodiments, the reaction conditions of step (b) comprise abase. The base may be an organic base (e.g., N,N-diisopropylethylamine,DBU and DMAP), an alkali metal base (e.g., NaH), a hexamethyldisilazanebase (e.g, sodium, potassium and lithium hexamethyldisilazide), acarbonate base (e.g., Cs₂CO₃, Na₂CO₃), and potassium tert-butoxide. Insome embodiments, the base may be N,N-diisopropylethylamine.

In some embodiments, the reaction conditions of step (b) the reactionconditions of step (b) comprise a solvent selected from the groupconsisting of toluene, tetrahydrofuran, 2-methyltetrahydrofuran,methyl-tert-butyl ether, acetonitrile, dioxane, benzene,dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone. Insome embodiments, the reaction conditions of step (b) comprise atemperature of about −78° C. to about 100° C. In some embodiments, thereaction conditions of step (b) comprise a temperature of about 90° C.to about 100° C.

In certain embodiments, the reaction conditions of step (c) comprise areagent selected from the group consisting of acetic anhydride andformic acid, acetic acid monoanhydride and carbonic acid, andtrifluoroacetic acid anhydride and formic acid.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of dichloromethane,chloroform, acetonitrile, isopropyl acetate, and tetrahydrofuran. Insome embodiments, the reaction conditions of step (c) comprise atemperature of about −10° C. to about 40° C. In some embodiments, thereaction conditions of step (c) comprise a temperature of about 0° C. toabout 5° C.

In certain embodiments, the reaction conditions of step (d) comprise anammonium reagent. The ammonium reagent may be ammonium acetate, ammoniumformate, or ammonium hydroxide. In some embodiments, the reactionconditions of step (d) comprise a solvent selected from the groupconsisting of acetic acid, toluene, benzene, and isopropanol. In someembodiments, the reaction conditions of step (d) comprise a temperatureof about 80° C. to about 120° C. In some embodiments, the reactionconditions of step (d) comprise a temperature of about 110° C. to about115° C.

In certain embodiments, the reaction conditions of step (e) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, i-PrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (e) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (e) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (f) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (f) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (f) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.

In some embodiments, the reaction conditions of step (f) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (f) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (g) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (g) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran,toluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (g) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(g) comprise a temperature of about 15° C. to about 25° C.

In one embodiment, provided is a process for preparing a compound offormula (A), salt thereof, or solvate thereof:

comprising the steps of:

(a) carboxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate or salt thereof:

(b) contacting a compound of formula (D) or a hydrate, solvate or saltthereof with propylphosphonic anhydride under reaction conditionssufficient to form a compound of formula (R):

and

(c) contacting a compound of formula (R) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

In some embodiments, a compound of formula (E) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrochloride salt.In some embodiments, a compound of formula (D) is a hydrate.

In some embodiments, a compound of formula (E) is synthesized accordingto any of the relevant methods described herein.

In certain embodiments, the reaction conditions of step (a) comprise abase. In some embodiments, the base may be an organolithium base, suchas MeLi, n-BuLi, t-BuLi, and sec-BuLi. In some embodiments, the base maybe a Grignard base (e.g., MeMgCl, i-PrMgCl, n-BuMgCl, and PhMgCl). Insome embodiments, the base may be isopropyl magnesium chloride.

In some embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether.

In some embodiments, the reaction conditions of step (a) comprise ametallation that occurs at a first temperature and a reaction with CO₂at a second temperature. In some embodiments, the first temperature isabout −20° C. to about 40° C., and the second temperature is about −10°C. to about 50° C. In some embodiments, the first temperature is about−5° C. to about 5° C., and the second temperature is about 10° C. toabout 20° C.

In certain embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane,tetrahydrofuran, dimethylformamide, ethyl acetate, methyl-tert-butylether, toluene, N-methyl-2-pyrrolidone, N,N-dimethyl acetamide,acetonitrile, dichloroethane, 2-methyltetrahydrofuran, and cyclopentylmethyl ether. In some embodiments, the reaction conditions of step (b)comprise a temperature of about −10° C. to about 60° C. In someembodiments, the reaction conditions of step (b) comprise a temperatureof about 0° C. to about 30° C. In some embodiments, the reactionconditions of step (b) comprise a temperature of about 20° C.

In certain embodiments, the reaction conditions of step (b) comprise atleast one organic base. The organic base may be organic amine, includingbut not limited to diisopropylethylamine, 4-dimethylaminopyridine,triethylamine, and N-methyl morpholine, and combinations thereof. Insome embodiments, the base may be a carbonate salt, including but notlimited to lithium carbonates, sodium carbonates, and cesium carbonates.

Scheme 2 represents an exemplary synthesis of a compound of formula (A)and can be carried out according to the embodiments described herein. Itis contemplated that this exemplary synthesis can provide a moretime-effective and convergent method for preparing Compound (D). It isalso contemplated that this synthesis exhibits the additional advantagesof utilizing hydrazide earlier in the synthetic route and employing lesstoxic starting materials (i.e., using Compound (H) in place of itscorresponding analog having bromide at the tosylate position). Theparticular reaction conditions and reagents employed in Scheme 2 arediscussed below.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) contacting a compound of formula (K) or a salt thereof:

with a compound of formula (L):

under reaction conditions sufficient to form a compound of formula (D)or a hydrate, solvate or salt thereof:

(b) chlorinating a compound of formula (D) or a hydrate, solvate or saltthereof under reaction conditions sufficient to form a compound offormula (B) or a salt thereof:

and

(c) contacting a compound of formula (B) or a salt thereof with acompound of formula (C) or a salt thereof:

under reaction conditions sufficient to yield a compound of formula (A).

wherein Z is a leaving group.

In some embodiments, the salt of compound (K) may be a besylate salt. Insome embodiments, the salt of compound (B) may be a hydrochloride salt.In some embodiments, the salt of compound (D) may be a hydrochloridesalt.

In some embodiments, Z may be a halogen, triflate, tosylate, boronateester, or boronic acid. In some embodiments, the boronate ester may beallylboronic acid pinacol ester. In some embodiments, Z may be —Cl, —Br,or —I. In some embodiments, Z may be a boronic acid.

In some embodiments, such as when Z may be a halogen, triflate, ortosylate, the reaction conditions of step (a) comprise a base. The basemay be a carbonate base (such as Cs₂CO₃, K₂CO₃ and Na₂CO₃) or aphosphate base (such as K₃PO₄ or Na₃PO₄). In such embodiments, thereaction conditions of step (a) comprise a catalyst. The catalyst may beCu₂O, CuOAc, CuI, CuBr, and [(CuOTf)₂-benzene complex]. In suchembodiments, a ligand may be included, such as 8-hydroxyquinoline,phenanthroline ligands (such as 4,7-dimethoxy-1,10-phenanthroline and1,10-phenanthroline), aminoarenethiols (such as2-((dimethylamino)methyl)benzenethiol), oxime-phosphine oxides,phosphoramidites, 2-aminopyrimidine diols (such as2-aminopyrimidine-4,6-diol), and oxime-phosphine oxides (such as2-hydroxybenzaldehyde oxime). Additives may also be included, such aspolyethyleneglycol and/or water, Et₄NHCO₃ and cetryltrimethylammoniumbromide.

In some embodiments, such as when Z may be a halogen, triflate, ortosylate, the reaction conditions of step (a) comprise a solventselected from the group consisting of N-methyl-2-pyrrolidone,dimethylforamide, N,N-dimethylacetamide, dimethylsulfoxide,butyronitrile, xylenes, propionitrile, dioxane, and toluene. In suchembodiments, the reaction conditions of step (a) comprise a temperatureof about 80° C. to about 150° C. In some embodiments, the reactionconditions of step (a) comprise a temperature of about 90° C. to about100° C.

In some embodiments, such as when Z may be a boronate ester or boronicacid, the reaction conditions of step (a) comprise a copper reagent andbase. The copper reagent may be Cu(OAc)₂, Cu(OTf)₂, Cu₂O, and CuBr. Thebase may be triethylamine, pyridine, or N,N-diisopropylethylamine. Insome embodiments, the reaction conditions of step (a) comprise a solventselected from the group consisting of methanol, dichloromethane, anddimethylformamide. In some embodiments, the reaction conditions of step(a) comprise a temperature of about 23° C. to about 100° C. In someembodiments, the reaction conditions of step (a) comprise a temperatureof about 23° C.

In certain embodiments, the reaction conditions of step (b) comprise achlorinating reagent. In some embodiments, the chlorinating reagent maybe oxalyl chloride with or without DMF, thionyl chloride, PCl₅, or PCl₃.

In some embodiments, the reaction conditions of step (b) comprise anadditive selected from the group consisting of trimethylsilyl chloride,water, HCl and tetrabutyl ammonium chloride.

In some embodiments, the reaction conditions of step (b) comprise asolvent selected from the group consisting of dichloromethane,acetonitrile, tetrahydrofuran, methyl-tert-butyl ether, and chloroform.In some embodiments, the reaction conditions of step (b) comprise atemperature of about −20° C. to about 40° C. In some embodiments, thereaction conditions of step (b) comprise a temperature of about 15° C.to about 25° C.

In certain embodiments, the reaction conditions of step (c) comprise anorganic base. The organic base may be N,N-diisopropylethylamine,triethylamine, pyridine, and 4-dimethylaminopyridine.

In some embodiments, the reaction conditions of step (c) comprise asolvent selected from the group consisting of dichloromethane,dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran,toluene, methyl-tert-butyl ether, and chloroform. In some embodiments,the reaction conditions of step (c) comprise a temperature of about 0°C. to about 40° C. In some embodiments, the reaction conditions of step(c) comprise a temperature of about 15° C. to about 25° C.

In certain embodiments, the process for preparing a compound of formula(A) further comprises forming a compound of formula (C), or a saltthereof, by:

(d) transforming a compound of formula (M):

under reaction conditions sufficient to form a compound of formula (C):

In such embodiments, the reaction conditions of step (d) comprise abase. The base may be cesium carbonate. In some embodiments, thereaction conditions of step (d) may comprise catalytic Pd(0) (e.g.Pd(dba)₂) or Pd(II) (e.g. Pd(OAc)₂) and a catalytic ligand (e.g.,P(t-Bu)₃ and rac-BINAP). In some embodiments, the reaction conditions ofstep (d) comprise a temperature of about 20° C. to about 90° C. Thesolvent may be toluene or dioxane.

In certain embodiments, the process for preparing a compound of formula(A) further comprises forming a compound of formula (M) by:

(e) contacting a compound of formula (O):

with a compound of formula (N):

under reaction conditions sufficient to form a compound of formula (M),wherein X is a halogen, triflate, or trifluoromethanesulfonate. In someembodiments, X may be iodo or bromo.

In such embodiments, the reaction conditions of step (e) comprise acatalyst. The catalyst may be PdCl₂(PPh₃) or other Pd (II) complexes orPd(0) complexes with trialkyl or triarylphosphine ligands. In someembodiments, the reaction conditions of step (e) comprise a co-catalyst.The co-catalyst may be CuI. In some embodiments, the reaction conditionsof step (e) comprise a base. The base may be a carbonate base, such asCs₂CO₃, K₂CO₃, and Na₂CO₃. In some embodiments, the reaction conditionsof step (e) comprise a solvent selected from the group consisting ofdioxane, dimethylformamide, dimethaylacetamide, dimethylsulfoxide,butyronitrile, and N-methyl-2-pyrrolidone. In some embodiments, thereaction conditions of step (d) comprise a temperature of about 80° C.to about 150° C. In some embodiments, the reaction conditions of step(d) comprise a temperature of about 95° C. to about 105° C.

In certain embodiments, the process for preparing a compound of formula(A) further comprises forming compound of formula (C), or a saltthereof, by:

(d) contacting a compound of formula (O):

with a compound of formula (P):

under reaction conditions sufficient to form a compound of formula (C).

wherein Y is a halogen, triflate, or trifluoromethanesulfonate. In someembodiments, Y may be chloro or bromo.

In some embodiments, the reaction conditions of step (d) comprise acatalyst, such as PdCl₂(PPh₃) or other Pd (II) complexes or Pd(0)complexes with trialkyl or triarylphosphine ligands. In someembodiments, the reaction conditions of step (d) comprise a co-catalyst.The co-catalyst may be CuI. In some embodiments, the reaction conditionsof step (d) comprise a base. The base may be a carbonate base, such asCs₂CO₃, K₂CO₃, and Na₂CO₃. In some embodiments, the reaction conditionsof step (d) comprise a solvent selected from the group consisting ofdioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide,butyronitrile, and N-methyl-2-pyrrolidone. In some embodiments, thereaction conditions of step (d) comprise a temperature of about 80° C.to about 150° C. In some embodiments, the reaction conditions of step(d) comprise a temperature of about 95° C. to about 105° C.

In some embodiments, the reaction conditions of step (d) comprise ametallation step followed by a coupling step. In such embodiments,during the metallation, the reaction conditions of step (d) comprise areagent selected from the group consisting of an organolithium reagent(such as n-BuLi, t-BuLi, MeLi, and s-BuLi) and a Grignard reagent (suchas iPrMgCl and PhMgCl). In some embodiments, the reaction conditions ofstep (d) comprise ZnCl₂, ZnCl₂ with LiCl, ZnBr₂, or ZnI₂. In someembodiments, the reaction conditions of step (d) comprise a solventselected from the group consisting of tetrahydrofuran,2-methyltetrahydrofuran, methyl-tert-butyl ether, and diethyl ether. Insome embodiments, during the coupling step, the reaction conditions ofstep (d) comprise a catalyst. The catalyst may be Pd(PPh₃)₄ or other Pd(II) complexes or Pd(0) complexes with trialkyl or triarylphosphineligands. In some embodiments, the reaction conditions of step (d)comprise a solvent selected from the group consisting of dioxane,N-methyl-2-pyrrolidone, tetrahydrofuran, butyronitrile, and toluene.

In some embodiments, the reaction conditions of step (d) comprise afirst temperature of about −78° C. to about −40° C. and a secondtemperature of about 80° C. to about 140° C. In some embodiments, thereaction conditions of step (d) comprise a first temperature of about−55° C. to about −60° C. and a second temperature of about 115° C. toabout 125° C. In such embodiments, the metallation occurs at the firsttemperature, and coupling reaction occurs at the second temperature.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (D), a salt thereof, or a solvatethereof:

comprising the steps of:

(a) carboalkoxylating a compound of formula (E) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (Q):

and

(b) hydrolyzing a compound of formula (Q) under reaction conditionssufficient to form a compound of formula (D), a hydrate, solvate or saltthereof.

In certain embodiments, the reaction conditions of step (a) comprise acatalyst and a base. The catalyst may be PdCl₂(PPh)₃ or other Pd (II)complexes or Pd(0) complexes. The base may be a carbonate base (such asK₂CO₃, Cs₂CO₃, and Na₂CO₃), an acetate (such as sodium acetate orpotassium acetate), or an organic base, such as(tetramethylethylenediamine, triethylamine, and diisopropylethyl amine).In some embodiments, the reaction conditions of step (a) comprise asolvent selected from the group consisting of butanol,dimethylformamide, and mixtures thereof. The reaction conditions of step(a) comprise a carbon monoxide pressure of about 5 psig to about 50 psigor about 5 psig. In some embodiments, the reaction conditions of step(a) comprise a temperature of about 70° C. to about 115° C. In someembodiments, the reaction conditions of step (a) comprise a temperatureof about 85° C. to about 95° C.

In certain embodiments, the reaction conditions of step (b) comprise abase. The base may be aqueous sodium hydroxide. In some embodiments, thereaction conditions of step (b) comprise a solvent selected from thegroup consisting of methanol, tetrahydrofuran, ethanol, propanol, andbutanol. In some embodiments, the reaction conditions of step (b)comprise a temperature of about 10° C. to about 60° C. In someembodiments, the reaction conditions of step (b) comprise a temperatureof about 20° C. to about 25° C.

Scheme 3 represents an exemplary synthesis of a compound of formula (A)and can be carried out according to the embodiments described herein.The particular reaction conditions and reagents employed in Scheme 3 arediscussed below.

In one embodiment, the present disclosure provides for a process forpreparing a compound of formula (A):

comprising the steps of:

(a) contacting a compound of formula (E) or a salt thereof:

with a compound of formula (C) or a salt thereof:

under reaction conditions sufficient to form a compound of formula (A).

In certain embodiments, the reaction conditions of step (a) comprise acatalyst. The catalyst may be Pd(OAc)₂ with Ad₂Pd(n-Bu) or other Pd (II)complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands,including but not limited to: Pd(dppf)Cl₂, PdCl₂ (PPh₃)₂, PdCl₂(PhCN)₂,PdCl₂(A-Phos)₂, Pd(OAc)₂/PPh₃, Pd(OAc)₂/PPh₃, Pd(OAc)₂/dppp,Pd(OAc)₂/xantphos, Pd(OAc)₂/t-Bu₃P. In some embodiments, the reactionconditions comprise a base. The base may be an organic base (such as antriethylamine, tetramethylethylenediamine, and diisopropylethyl amine),a carbonate base (such as Cs₂CO₃, K₂CO₃ and Na₂CO₃), or an acetate base(such as sodium acetate or potassium acetate). In some embodiments, thereaction conditions comprise a solvent selected from the groupconsisting of dimethylformamide, N-methyl-2-pyrrolidone, dioxane, andtoluene. In some embodiments, the reaction conditions comprise atemperature of about 90° C. to about 120° C. In some embodiments, thereaction conditions comprise a temperature of about 100° C. In someembodiments, the reaction conditions comprise a carbon monoxide pressureof about 20 psig to about 60 psig or about 20 psig.

Compounds

In other embodiments, the disclosure provides for intermediate compoundsthat are useful in the processes described herein. Thus, for instance,one embodiment is a compound of the formula (B) or a salt thereof:

In some embodiments, a compound of formula (B) may be a hydrochloridesalt.

Another embodiment is a compound of formula (M):

Also provided herein are compounds of formula (Q):

Also provided herein are compounds of formula (G):

Also provided herein are compounds of formula (F):

Also provided herein are compounds of formula (E):

Also provided herein are compounds of formula (D):

In some embodiments, a compound of formula (D) may be a hydrochloridesalt. Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acidhydrochloride (Compound of formula (D-a) Form I) characterized by anX-ray powder diffractogram comprising the following peaks: 7.3, 22.3,23.4, 23.9, and 26.8 °2θ±0.2 °2θ, as determined on a diffractometerusing Cu—Kα radiation at a wavelength of 1.5406 Å. The diffractogramcomprises additional peaks at 11.5, 13.4, 20.9, and 22.0 °2θ±0.2 °2θ.Compound of formula (D-a) Form I is also characterized by its full X-raypowder diffractogram as substantially shown in FIG. 1. In someembodiments, the diffractogram of a compound of formula (D-a) Form Icomprises the following peaks: 7.3, 8.9, 11.5, 13.4, 17.1, 17.8, 18.6,20.9, 22.0, 22.3, 23.4, 23.9, 26.8, 27.5, 29.6, 31.1, 32.0, and 35.4°2θ±0.2 °2θ. In some embodiments, a compound of formula (D-a) Form I ischaracterized by a differential scanning calorimetry (DSC) curve thatcomprises an endotherm at about 210° C. Compound of formula (D-a) Form Iis characterized by its full DSC curve as substantially shown in FIG. 2.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acidhydrochloride (Compound of formula (D-a) Form II) characterized by anX-ray powder diffractogram comprising the following peaks: 8.7, 12.1,25.7, and 26.3 °2θ±0.2 °2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.5406 Å. The diffractogram comprisesadditional peaks at 17.3, 19.0, 22.4, 28.6, and 29.7 °2θ±0.2 °2θ.Compound of formula (D-a) Form II is also characterized by its fullX-ray powder diffractogram as substantially shown in FIG. 4. In someembodiments, the diffractogram of a compound of formula (D-a) Form IIcomprises the following peaks: 8.7, 9.2, 12.1, 17.3, 18.3, 18.6, 19.0,20.9, 21.1, 21.5, 22.4, 24.2, 25.7, 26.3, 26.7, 28.6, and 29.7 °2θ±0.2°2θ. In some embodiments, a compound of formula (D-a) Form II ischaracterized by a differential scanning calorimetry (DSC) curve thatcomprises an endotherm at about 217° C. Compound of formula (D-a) FormII is characterized by its full DSC curve as substantially shown in FIG.5.

In some embodiments, a compound of formula (D) may be a hydrate. Anotherembodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid hydrate(Compound of formula (D) hydrate Form I) characterized by an X-raypowder diffractogram comprising the following peaks: 9.5, 20.4, 24.3,26.5, and 28.7 °2θ±0.2 °2θ, as determined on a diffractometer usingCu—Kα radiation at a wavelength of 1.5406 Å. The diffractogram comprisesadditional peaks at 11.5, 12.8, 13.2, 15.9, 18.5, and 19.0 °2θ±0.2 °2θ.Compound of formula (D) hydrate Form I is also characterized by its fullX-ray powder diffractogram as substantially shown in FIG. 7. In someembodiments, the diffractogram of a compound of formula (D) hydrate FormI comprises the following peaks: 9.5, 11.5, 12.8, 13.2, 14.1, 15.9,17.1, 17.2, 18.5, 19.0, 19.8, 20.4, 22.8, 23.0, 24.3, 24.6, 25.0, 25.6,26.5, 26.8, 28.7, 29.1, and 30.6 °2θ±0.2 °2θ. In some embodiments, acompound of formula (D) hydrate Form I is characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 252° C. In some embodiments, the DSC curve furthercomprises an endotherm at about 89° C. Compound of formula (D) hydrateForm I is characterized by its full DSC curve as substantially shown inFIG. 8.

In some embodiments, a compound of formula (D) may be anhydrous. Anotherembodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form I) characterized by an X-ray powder diffractogramcomprising the following peaks: 8.7, 15.2, 21.5, and 23.8 °2θ±0.2 °2θ,as determined on a diffractometer using Cu—Kα radiation at a wavelengthof 1.5406 Å. The diffractogram comprises additional peaks at 12.4, 14.0,14.1, 17.4, and 26.2 °2θ±0.2 °2θ. Compound of formula (D) Form I is alsocharacterized by its full X-ray powder diffractogram as substantiallyshown in FIG. 10. In some embodiments, the diffractogram of a compoundof formula (D) Form I comprises the following peaks: 8.7, 12.4, 14.0,14.1, 15.2, 17.4, 17.9, 18.2, 20.5, 21.5, 22.3, 22.7, 23.3, 23.8, 24.4,26.2, 28.1, 28.4, and 29.2 °2θ±0.2 °2θ. In some embodiments, a compoundof formula (D) Form I is characterized by a differential scanningcalorimetry (DSC) curve that comprises an endotherm at about 252° C.Compound of formula (D) Form I is characterized by its full DSC curve assubstantially shown in FIG. 11.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form II) characterized by a calculated X-ray powderdiffractogram comprising the following peaks: 8.4, 13.6, and 15.5°2θ±0.2 °2θ, as determined on a diffractometer using Cu—Kα radiation ata wavelength of 1.5406 Å. The calculated diffractogram comprisesadditional peaks at 9.8, 13.6, and 25.4 °2θ±0.2 °2θ. A mixture ofcompound of formula (D) Form II and compound of formula (D) Form I isalso characterized by its full X-ray powder diffractogram assubstantially shown in FIG. 18. In some embodiments, the calculateddiffractogram of a compound of formula (D) Form I comprises thefollowing peaks: 5.2, 8.4, 9.8, 10.4, 13.2, 13.6, 14.4, 15.5, 19.5,25.0, 25.4, and 27.5 °2θ±0.2 °2θ. In some embodiments, a mixture of acompound of formula (D) Form I and Compound of formula (D) Form II ischaracterized by a differential scanning calorimetry (DSC) curve thatcomprises an endotherm at about 252° C. In some embodiments, the DSCcurve further comprises an endotherm at about 131° C. A mixture of acompound of formula (D) Form I and Compound of formula (D) Form II ischaracterized by its full DSC curve as substantially shown in FIG. 17.

Another embodiment is crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acid (Compoundof formula (D) Form III) characterized by an X-ray powder diffractogramcomprising the following peaks: 10.3, 17.1, 18.0, and 25.7 °2θ±0.2 °2θ,as determined on a diffractometer using Cu—Kα radiation at a wavelengthof 1.5406 Å. The diffractogram comprises additional peaks at 20.6, 24.2,24.6, and 25.2 °2θ±0.2 °2θ. Compound of formula (D) Form III is alsocharacterized by its full X-ray powder diffractogram as substantiallyshown in FIG. 13. In some embodiments, the diffractogram of a compoundof formula (D) Form III comprises the following peaks: 8.6, 10.3, 13.8,14.0, 17.1, 18.0, 20.6, 21.3, 24.2, 24.6, 25.2, 25.7, 26.3, 26.7, 28.2,and 29.6 °2θ±0.2 °2θ. In some embodiments, a compound of formula (D)Form III is characterized by a differential scanning calorimetry (DSC)curve that comprises an endotherm at about 253° C. In some embodiments,the DSC curve further comprises an endotherm at about 164° C. Compoundof formula (D) Form III is characterized by its full DSC curve assubstantially shown in FIG. 14.

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of compounds described herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers. Unless otherwise noted, the starting materials forthe following reactions may be obtained from commercial sources.

Example 1 Synthesis of Compound (A)

Hydroxytosylation of Compound (J) to Form Compound (H)

Koser's reagent, PhI(OH)OTs, (1.0 eq.) and acetonitrile (5 vols) arecharged to a flask. Cyclopropylmethyl ketone (Compound (J), 1.2 eq.) ischarged and the mixture is heated to about 70° C. to about 75° C. Oncethe reaction is complete, the contents are cooled and concentrated. Theresidue is diluted in dichloromethane (about 2.5 vols) and washed withwater (2× about 1 to 2 volumes). The organic phase is concentrated toapproximately 1.5 vols and the product is triturated with hexanes (about1.5 to 2 vols) and concentrated to remove dichloromethane and thedistilled volume is replaced with hexanes. The slurry is agitated forabout two hours, filtered and washed with hexanes. The solids are driedunder vacuum at about 40° C. to afford Compound (H). ¹H NMR (400 MHz,DMSO-d₆): δ 7.82 (d, 2H, J=8.0 Hz), 7.49 (d, 2H, J=8.0 Hz), 4.98 (s,2H), 2.42 (s, 3H), 2.02-2.08 (m, 1H), 0.95-0.91 (m, 2H), 0.89-0.82 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆): 202.39, 145.60, 132.76, 130.57, 128.12,72.98, 21.52, 17.41, 11.39.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of Koser's reagent,alternative reagents may include, but are not limited to,(diacetoxyiodo)benzene organosulfonic acid, (diacetoxyiodo)benzene andp-toluenesulfonic acid, iodosylbenzene/p-toluenesulfonic acid,m-chloroperbenzoic acid/p-toluenesulfonic acid, poly(4-hydroxytosyloxyiodo)styrenes, N-methyl-O-tosylhydroxylamine, Dess-Martinperiodinane/p-toluenesulfonic acid, HIO₃/p-toluenesulfonic acid, ando-iodoxybenzoic acid/p-toluenesulfonic acid. Various solvents, such astoluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran,dichloromethane, and chloroform, may be employed. The reaction may takeplace at temperatures that range from about 20° C. to about 100° C.

Alkylation of Compound (H) with Compound (I) to Form Compound (G)

To a mixture of Compound (I) (1.0 equiv) and Compound (H) (1.1 equiv) intoluene (5 vols) is charged iPr₂NEt (2.1 equiv). The mixture is heatedto about 90 to about 100° C. and aged for about less than 10 hours. Uponcompletion, the mixture is cooled and diluted with water (about 5 toabout 6 vols). The biphasic mixture is separated and the organicsolution is washed sequentially with aq. NH₄Cl (about 27 wt %, about 2to about 3 vols), aq. NaHCO₃ (about 9 wt %, about 2 to about 3 vols),and aq. NaCl (about 15 wt %, about 1 vols). The organic solution isdried over Na₂SO₄, filtered, and washed with toluene (about 2 to about 3vols). The solution is concentrated under vacuum at about 45° C. and theresidue is crystallized by the addition of hexane at about 20° C. toabout 25° C. and at about 10° C. to about 15° C. The slurry is filtered,washed with cooled isopropanol (about 1 vol) and dried under vacuum atabout 37° C. to about 43° C. to afford Compound (G). ¹H NMR (400 MHz,DMSO-d₆): δ 7.05 (d, 1H, J=12.0 Hz), 6.51 (d, 1H, J=8.0 Hz), 5.27 (t,1H, J=4.0 Hz), 4.17 (d, 2H, J=4.0 Hz), 2.21-2.14 (m, 1H), 2.10 (s, 3H),0.96-0.86 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆): 208.17, 151.63, 149.32,143.99, 143.97, 123.81, 123.74, 118.13, 117.90, 112.87, 105.09, 104.88,53.72, 18.33, 17.43, 17.42, 10.85.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases, including but notlimited to organic bases (e.g., DBU and DMAP), alkali metal bases (e.g.,NaH), hexamethyldisilazane bases (e.g, sodium, potassium and lithiumhexamethyldisilazide), carbonate bases (e.g., Cs₂CO₃, Na₂CO₃), andpotassium tert-butoxide. Various solvents, such as THF, MTBE, 2-MeTHF,acetonitrile, dioxane, benzene, DMF, DMAc, NMP, may be employed. Thereaction may take place at temperatures that range from about −78° C. toabout 100° C.

Formylation of Compound (G) to Form Compound (F)

Acetic anhydride (4 equiv) is added to aqueous formic acid (about 3 toabout 4 vols) at about 0° C. to about 5° C. and the mixture is agitated.Compound (G) (1.0 equiv) in DCM (about 3 vols) is charged. The reactionis aged at about 0 to about 5° C. until it is deemed complete. Uponreaction completion, water (about 4 vols) is charged and the mixture isadjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH with thecontent temperature maintained between about 0° C. to about 15° C. Thebiphasic mixture is separated and the aqueous solution is extracted withdichloromethane (about 6 vols). The organic solution is washed withsaturated aqueous NaCl (about 4 vols), dried over Na₂SO₄, and filtered.Compound (F) is carried forward to the next step as a solution indichloromethane without further purification. ¹H NMR (400 MHz, DMSO-d₅):δ (mixture of amide rotamers) 8.17 (s, 1H), 8.14 (s, 1H), 7.61 (d, 1H,J=8.0 Hz), 7.45 (d, 1H, J=8.0 Hz), 7.42 (d, 1H, J=12.0 Hz), 7.33 (d, 1H,J=12.0 Hz), 4.87 (s, 2H), 4.68 (s, 2H), 2.25 (s, 3H), 2.16 (s, 3H),2.12-2.03 (m, 1H), 0.98-0.85 (m, 4H). ¹³C NMR (100 MHz, DMSO-d₆): 206.68(204.85), 163.71 (163.22), 158.95 (158.69), 156.51 (156.35), 139.09(139.02), 138.61 (138.53), 137.58 (137.55), 133.35 (133.34), 132.45,119.02 (118.79), 118.58 (118.36), 105.35 (105.03), 104.77 (104.55),58.68, 55.40, 17.84 (17.77).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of acetic anhydride andformic acid, acetic acid monoanhydride with carbonic acid ortrifluoroacetic anhydride with formic acid may be used. Varioussolvents, such as chloroform, acetonitrile, isopropyl acetate, or THF,may be employed. The reaction may take place at temperatures that rangefrom about −10° C. to about 40° C.

Imidazole Cyclization to Form Compound (E)

To a solution of Compound (F) (1.0 equiv) in DCM is charged acetic acid(about 5 vols). The solution is concentrated under vacuum at about 35°C. to remove the bulk of DCM and ammonium acetate (3.9 equiv) is added.The mixture is heated to about 110° C. to about 115° C. and agitateduntil the reaction is deemed complete. The reaction is cooled, dilutedwith water (about 10 vols) and iPrOAc (about 6 vols). The mixture isadjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH. Thebiphasic mixture is separated. Sodium chloride (about 0.3 wt equiv wrtCompound (F)) is charged to the aqueous layer and the aqueous layer isextracted with iPrOAc (about 2 vols). The organic solution is washedwith water (about 5 vols) and aq. NaCl (about 10 wt %, about 4 to about5 vols). The solution is concentrated under vacuum and solvent exchangedto about 2-3 vols N,N-dimethylacetamide (DMAc). Water (about 5 to about6 vols) is charged to afford Compound (E) as a slurry. The slurry isfiltered and washed sequentially with DMAc/water, water, and hexanes.The resulting solids are dried under vacuum at about 55° C. to affordCompound (E). ¹H NMR (400 MHz, DMSO-d₆): δ 7.68 (d, 1H, J=4.0 Hz), 7.64(d, 1H, J=1.0 Hz), 7.46 (d, 1H, J=12.0 Hz), 7.12 (d, 1H, J=1.0 Hz), 2.12(s, 3H), 1.85-1.79 (m, 1H), 0.81-0.76 (m, 2H), 0.70-0.66 (2H). ¹³C NMR(100 MHz, DMSO-d₆): 159.11, 156.67, 156.67, 143.94, 137.36, 136.19,136.11, 134.44, 134.41, 131.21, 131.20, 119.05, 118.82, 116.21, 105.56,105.34, 17.72, 17.71, 9.26, 7.44.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of ammonium acetate,alternative sources of ammonia may be used, including but not limited toammonium formate and ammonium hydroxide. Various solvents, such astoluene, benzene, and isopropanol, may be employed. The reaction maytake place at temperatures that range from about 80° C. to about 120° C.

Carboxylation of Compound (E) to Form Compound (D)

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooledto about −10 to about 0° C. and a solution of iPrMgCl (2.0 M in THF, 1.2equiv) was charged slowly to maintain the internal temperature belowabout 5° C. The mixture was stirred for about 1 hour at about −5 toabout 5° C. after which CO₂ was bubbled slowly into the mixture(exothermic). The addition is continued until the exotherm subsides andthe internal temperature typically increases to about 15 to about 25° C.after the addition. Upon reaction completion, the mixture isconcentrated under vacuum to approximately 3 vols and water (about 6 toabout 7 vols) is added, followed by about 1 vol 6M HCl. MTBE (about 10vols) is added and the biphasic mixture is separated. A solution of 6 MHCl is added slowly to the aqueous layer to adjust the pH (initiallyat >10) to approximately 4.8. The mixture is seeded with Compound (D)(if necessary), which was formed according to the procedure outlinedabove, and the resultant slurry is cooled slowly to about 0° C. to about5° C. and aged. The slurry is filtered, washed with water (about 4vols), isopropanol (about 4 vols), followed by n-heptane (about 6 vols).The solids are dried under vacuum at about 40° C. to afford Compound(D). ¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (d, 1H, J=2.0 Hz), 7.67 (d, 1H,J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.15 (d, 1H, J=2.0 Hz), 2.20 (s, 3H),1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). ¹³C NMR (100MHz, DMSO-d₆): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53,137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25,18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases, including but notlimited to organolithium bases (e.g., MeLi, n-BuLi, t-BuLi, andsec-BuLi) and Grignard bases (e.g., MeMgCl, n-BuMgCl, and PhMgCl).Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et₂O, may beemployed. The reaction may initially take place at temperatures thatrange from about −20° C. to about 40° C. and then continue attemperature that range from about −10° C. to about 50° C.

Conversion of Compound (D) to Form Compound (D-a)

To a mixture of Compound (D) (1.0 equiv) in methanol (about 4 vols) atabout 15° C. to about 25° C. is charged concentrated HCl (1.1 equivrelative to Compound (D)). The mixture is aged until most of theCompound (D) is dissolved, seeded with Compound (D-a) (0.005 equiv),which was formed according to the procedure outlined above, and MTBE(about 3 vols relative to the amount of seed) is charged slowly. Theslurry is aged, filtered, and rinsed with MTBE (5 vols) and the solidsare dried under vacuum at about 40° C. to afford Compound (D-a). ¹H NMR(400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.00 (d, 1H, J=8.0 Hz), 7.76 (d, 1H,J=2.0 Hz), 7.54 (d, 1H, J=12.0 Hz), 2.25 (s, 3H), 2.08-2.01 (m, 1H),1.05-1.00 (m, 2H), 0.92-0.88 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆):164.08, 164.05, 162.73, 160.14, 142.11, 142.01, 137.11, 135.91, 131.14,131.11, 130.73, 120.19, 119.96, 118.78, 118.39, 118.27, 17.71, 8.24,6.13.

Carboxylation of Compound (E) to Form Compound (D) Hydrate

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooledto about −10 to about 0° C. and a solution of iPrMgCl (2.0 M in THF, 1.2equiv) was charged slowly to maintain the internal temperature belowabout 5° C. The mixture was stirred for about 1 hour at about −5 toabout 5° C. after which CO₂ was bubbled slowly into the mixture(exothermic). The addition is continued until the exotherm subsides andthe internal temperature typically increases to about 15 to about 25° C.after the addition. Upon reaction completion, the mixture isconcentrated under vacuum to approximately 3 vols and water (about 6 toabout 7 vols) is added, followed by about 1 vol 6 M HCl. MTBE (about 10vols) is added and the biphasic mixture is separated. A solution of 6 MHCl is added slowly to the aqueous layer to adjust the pH (initiallyat >10) to approximately 4.8. The mixture is seeded with Compound (D)(if necessary), which was formed according to the procedure outlinedabove, and the resultant slurry is cooled slowly to about 0° C. to about5° C. and aged. The slurry is filtered and washed with water (about 4vols). The solids are dried under vacuum at about 40° C. to affordCompound (D) hydrate. ¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (d, 1H, J=2.0Hz), 7.67 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.15 (d, 1H, J=2.0Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m,2H). ¹³C NMR (100 MHz, DMSO-d₆): 164.52, 164.48, 161.68, 159.12, 143.95,141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08,117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases, including but notlimited to organolithium bases (e.g., MeLi, n-BuLi, t-BuLi, andsec-BuLi) and Grignard bases (e.g., MeMgCl, n-BuMgCl, and PhMgCl).Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et₂O, may beemployed. The reaction may initially take place at temperatures thatrange from about −20° C. to about 40° C. and then continue attemperature that range from about −10° C. to about 50° C.

Acid Chloride Formation Using Compound (D-a) to Form Compound (B)

To a mixture of Compound (D-a) (1.0 equiv), DCM (about 10 vols) and DMF(0.1 equiv), a solution of oxalyl chloride (about 1.7 equiv) was slowlycharged to maintain the internal temperature below about 30° C. Themixture was stirred for about 1 hour at about 20° C. after which timethe mixture is distilled to about 4 vols total volume. DCM (about 5vols) is repeatedly charged and the mixture distilled to about 4 volstotal volume. DCM is then charged to bring the total volume to about 12vols of Compound (B). The solution is carried forward to the next stepwithout further purification.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of Compound (D-a), compound(D) may be used. Additionally, in lieu of oxalyl chloride and DMF,thionyl chloride, PCl₅, and PCl₃ may be used. Various solvents, such asMeCN, THF, and MTBE, may be employed. In some embodiments, additives maybe used, including but not limited to trimethylsilyl chloride, water,HCl, or tetrabutyl ammonium chloride. The reaction may take place attemperatures that range from about −20° C. to about 40° C.

Acid Chloride Formation Using Compound (D) Hydrate to Form Compound (B)

To a mixture of Compound (D) hydrate (1.0 equiv), DCM (about 10 vols)and DMF (0.1 equiv), a solution of oxalyl chloride (1.2 equiv) wasslowly charged to maintain the internal temperature below about 30° C.The mixture was stirred for about 1 hour at about 20° C. after whichtime the mixture is distilled to about 4 vols total volume. DCM (about 5vols) is repeatedly charged and the mixture distilled to about 4 volstotal volume. DCM is then charged to bring the total volume to about 12vols of Compound (B). The solution is carried forward to the next stepwithout further purification.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of Compound (D) hydrate,compound (D) may be used. Additionally, in lieu of oxalyl chloride andDMF, thionyl chloride, PCl₅, and PCl₃ may be used. Various solvents,such as MeCN, THF, and MTBE, may be employed. In some embodiments,additives may be used, including but not limited to trimethylsilylchloride, water, HCl, or tetrabutyl ammonium chloride. The reaction maytake place at temperatures that range from about −20° C. to about 40° C.

Amide Bond Formation to Form Compound (A)

Compound (C) was synthesized as described in U.S. Pat. No. 8,742,126,which is hereby incorporated by reference in its entirety.

To a solution of Compound (B) (about 1 equiv in about 12 vols DCM) wascharged diisopropylethyl amine (1.0 equiv) followed by Compound (C)(1.05 equiv). Upon reaction completion, 5% aqueous sodium hydroxide(about 5 vols) is added and the layers of the biphasic mixture areseparated. A solution of 10% aqueous citric acid (about 2 vols) ischarged to the organic layer and the layers of the biphasic mixture areseparated. Water (about 5 vols) is charged to the organic layer and thelayers of the biphasic mixture are separated. The organic solution isfiltered, and the solution is solvent swapped to about 15% DCM in EtOHunder vacuum at about 45° C. The mixture is seeded with about 0.00.1equiv of Compound (A), which was synthesized as described by U.S. Pat.No. 8,742,126, and the resultant slurry is aged at about 45° C. Anadditional 2-3 vols solvent is distilled in vacuo and then heptane(about 10 vols) is charged slowly and the slurry is aged, cooled toabout 20° C., filtered and washed with 1:2 EtOH:heptane (about 3 vols).The solids are dried under vacuum at about 40° C. to afford Compound(A). Characterization data for Compound (A) matches that disclosed inU.S. Pat. No. 8,742,126.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases may be used,including but not limited to Et₃N, pyridine, and DMAP. Various solvents,such as 2-MeTHF, toluene, MTBE, and chloroform, may be employed. Thereaction may take place at temperatures that range from about 0° C. toabout 40° C.

In lieu of Compound (B), Compound (D) or activated esters thereof may beemployed. Coupling reagents may also be employed; non-limiting examplesof such reagents include propane phosphonic acid anhydride (T3P®),1,1′-carbonyldiimidazole, EDC/HOBt or other imide coupling reagents,isobutylchloroformate (to generate an isobutyl ester), and pivoylchloride (to generate a pivalate ester).

Example 2 Alternative Synthesis of Compound (D)

Coupling of Compound (K) and Compound (L-a) to Provide Compound (D)

Compound (L-a) (1.0 eq), Compound (K) (1.5 eq), potassium phosphate (5.0eq), copper (I) oxide (0.05 eq), and 8-hydroxyquinoline, Compound 2-2(0.2 eq) were combined with degassed DMSO (about 6 vols). The reactionmixture was heated to about 95° C. to about 105° C. and stirred forabout 22 h. Upon reaction completion, the mixture was cooled to ambienttemperature and diluted with water (about 6 vols) and isopropyl acetate(about 5 vols). The aqueous layer was washed with isopropyl acetate(about 5 vols), and the pH was adjusted to about 6 by the addition of 8M HCl. The solution was seeded with about 0.003 equiv of Compound (D)seed, which was synthesized as described in U.S. Pat. No. 8,742,126, andthe pH was further adjusted to pH about 4.8. The resultant slurry wascooled to about 0° C. for about 2 h, filtered, and washed with colddilute HCl (pH about 4.8, about 2 vols) and cold isopropyl alcohol(about 2 vols) to provide Compound (D). ¹H NMR (400 MHz, DMSO-d₆): δ7.69 (d, 1H, J=2.0 Hz), 7.67 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz),7.15 (d, 1H, J=2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m,2H), 0.71-0.67 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 164.52, 164.48,161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70,119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative bases may be used,including but not limited to carbonate bases (such as Cs₂CO₃, K₂CO₃, andNa₂CO₃). In lieu of Cu₂O, alternative catalysts may be used, such asCuOAc, CuI, CuBr, and [(CuOTf)₂-benzene complex]. Non-limiting examplesof alternative ligands include phenanthroline ligands (such as4,7-dimethoxy-1,10-phenanthroline (Compound 2-1) and1,10-phenanthroline), aminoarenethiols (such as2-((dimethylamino)methyl)benzenethiol), oxime-phosphine oxides,phosphoramidites, 2-aminopyrimidine diols (such as2-aminopyrimidine-4,6-diol), and oxime-phosphine oxides (such as2-hydroxybenzaldehyde oxime). In some embodiments, additives may beused, including but not limited to polyethyleneglycol and/or water,Et₄NHCO₃, and cetryltrimethylammonium bromide.

In lieu of Compound (L-a), alternative starting material can be used,including but not limited to 5-bromo-2-fluoro-4-methylbenzoic acid,2-fluoro-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoic acid, and2-fluoro-4-methyl-5-(tosyloxy)benzoic acid. Additionally, in lieu of thefree base of Compound (K), various salts of Compound (K) may be used,such as the besylate salt.

Various solvents may be used, including but not limited to DMF, DMAc,DMSO, butyronitrile, xylenes, EtCN, dioxane, and toluene. The reactionmay take place at temperatures that range from about 80° C. to about150° C.

Coupling of Compound (L-b) with Compound (K) to Provide Compound (D)

Compound (L-b) (1 equiv), Compound (K) (1.2 equiv), and Cu(OAc)₂ (1equiv) was added methanol (about 20 vols) followed by pyridine (2.2equiv). The mixture was then stirred at about 23° C. for about 16 h,then at about 45° C. for about 4 h. The reaction mixture was dilutedwith methanol (about 60 vols), filtered though a pad of celite andconcentrated in vacuo to afford Compound (D). ¹H NMR (400 MHz, DMSO-d₆):δ 7.69 (d, 1H, J=2.0 Hz), 7.67 (d, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0Hz), 7.15 (d, 1H, J=2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77(m, 2H), 0.71-0.67 (m, 2H). ¹³C NMR (100 MHz, DMSO-d₆): 164.52, 164.48,161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70,119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of Compound (L-b),2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid may be used. In lieu of Compound (K), the besylate salt of Compound(K) may be used.

Various copper reagents can be employed, such as Cu(OTf)₂, Cu₂O, andCuBr. Alternative bases include but are not limited to triethylamine andN,N-diisopropylethylamine. Various solvents, such as DCM and DMF, may beemployed. The reaction may take place at temperatures that range fromabout 23° C. to about 100° C. and under an atmosphere of oxygen ornitrogen.

Example 3 Alternative Synthesis of Compound (C)

Coupling of Compound (O) with Compound (N-a) to Form Compound (M)

To a mixture of Compound (O) (1.0 equiv), Compound (N-a) (1.6 equiv),PdCl₂(PPh₃)₂ (65 mol %), Cs₂CO₃ (2.0 equiv), and CuI (4.7 mol %) wascharged dioxane (10 mL). The mixture was degassed and then heated toabout 95° C. to about 105° C. After a period of about 20 hours, themixture was cooled to ambient temperature. The reaction mixture wasdiluted with EtOAc (about 10 vols), washed with water (about 10 vols)and the layers of the biphasic mixture were separated. The organic layerwas dried over MgSO₄ and concentrated in vacuo. The crude residue waspurified by silica gel chromatography to afford Compound (M). ¹H NMR(400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.16-8.04 (m, 2H), 7.67 (d, 1H,J=8.4 Hz), 5.34 (sep, 1H, J=6.6 Hz), 1.50 (d, 6H, 6.6 Hz). ¹³C NMR (100MHz, DMSO-d₆): 149.90, 149.58, 148.36, 144.11, 141.62, 125.27, 122.92,48.91, 23.42.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts may be other Pd(II) complexes or Pd(0) complexes with trialkyl or triarylphosphineligands, including but not limited to: Pd(PPh₃)₄, Pd₂dba₃/PPh₃,Pd(OAc)₂/dppf, Pd₂dba₃/dppp, Pd(OAc)₂/PPh₃, Pd(OAc)₂/dppe, Pd₂dba₃/dppf.Various bases may be used, such as a carbonate base (e.g. K₂CO₃ orNa₂CO₃). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, andNMP, may be employed. The reaction may take place at temperatures thatrange from about 80° C. to about 150° C.

Conversion of Compound (M) to Form Compound (C)

To a mixture of Compound (M) (1.0 equiv), Pd(OAc)₂ (2.0 mol %),rac-BINAP (3.0 mol %), and Cs₂CO₃ (1.4 equiv), was charged dioxane(about 9 vols) followed by benzophenone imine (2.0 equiv). The mixturewas degassed, sealed and then heated to about 75° C. to about 85° C.under nitrogen. After a period of about 20 hours, the mixture was cooledto ambient temperature, and HCl (6 M, about 8 vols) was charged untilthe pH of the reaction mixture was about 1 to about 2. The solution wasmaintained at ambient temperature for about 15 minutes, then NaOH (30wt. %, about 1 to about 2 vols) was charged until the pH of the reactionmixture was about 8-9. The reaction mixture was concentrated in vacuo,slurried in MeOH (about 22 vols), and filtered to remove gross solids,which were washed with MeOH (2× about 3 vols). The resulting solutionwas concentrated in vacuo, adsorbed onto celite and purified by silicagel chromatography to provide compound (C). LRMS [M+H]⁺: 204.08.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts may be other Pd(II) complexes or Pd(0) complexes with trialkyl or triarylphosphineligands, including but not limited to: Pd(PPh₃)₄, Pd₂dba₃/PPh₃,Pd(OAc)₂/dppf, Pd₂dba₃/dppp, Pd(OAc)₂/PPh₃, Pd(OAc)₂/dppe, Pd₂dba₃/dppf,Pd₂dba₃/CyJohnPhos, Pd₂dba₃/P(t-Bu)₃. Various ammonia sources may beused such as LiHMDS or ammonium hydroxide. Various carbonate bases (e.g.K₂CO₃ or Na₂CO₃) or phosphate bases such as K₃PO₄ may be used. Varioussolvents, such as THF, DMAc, DMSO, and NMP, may be employed. Thereaction may take place at temperatures that range from about 75° C. toabout 150° C. and pressures ranging from about 15 to about 50 psig.

Example 4 Alternative Synthesis of Compound (C)

Coupling of Compound (O) with Compound (P-a) to Form Compound (C)

To a mixture of Compound (O) (1.0 equiv), Compound (P-a) (1.0 equiv),PdCl₂(PPh₃)₂ (10 mol %), Cs₂CO₃ (2.0 equiv), and CuI (4.7 mol %) wascharged dioxane (about 20 vols). The mixture was degassed and thenheated to about 95° C. to about 105° C. After a period of about 20 toabout 40 hours, the mixture was cooled to ambient temperature. Thereaction mixture was diluted with EtOAc (about 40 vols) and the organiclayer was washed with water (about 40 vols). The layers of the biphasicmixture were separated and the aqueous phase was extracted with EtOAc(about 40 vols). The combined organic phases were concentrated in vacuo.To the residue was charged IPA (about 20 vols), and the resultingsuspension was stirred at about 40° C. to about 50° C. for about 1 h andthen stirred at ambient temperature for about 16 h. The suspension wascooled to about 5° C., filtered and washed with cold IPA (about 4 vols).The resulting solids were dried at about 40° C. to afford Compound (C).¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 7.51 (t, 1H, J=8.0 Hz), 7.18(d, 1H, J=4.0 Hz), 6.53 (d, 1H, J=8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H,J=8.0 Hz), 1.42 (d, 6H, J=8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): 159.59,151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts may be other Pd(II) complexes or Pd(0) complexes with trialkyl or triarylphosphineligands, including but not limited to: Pd(PPh₃)₄, Pd₂dba₃/PPh₃,Pd(OAc)₂/dppf, Pd₂dba₃/dppp; Pd(OAc)₂/PPh₃; Pd(OAc)₂/dppe; Pd₂dba₃/dppf,Pd(OAc)₂/(m-tolyl)₃P, Pd(OAc)₂/JohnPhos; PdCl₂dppf,Pd(OAc)₂/(o-tolyl)₃P; PdCl₂(AmPhos)₂; Pd(OAc) 2/(cyclohexanlyl)₃P.Various bases may be used, such as a carbonate base (e.g. K₂CO₃ orNa₂CO₃). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, andNMP, may be employed. The reaction may take place at temperatures thatrange from about 80° C. to about 150° C.

Coupling of Compound (O) with Compound (P-b) to Form Compound (C)

A solution of Compound (O) (1.0 equiv) in THF (about 20 vols) wasdegassed with nitrogen. The solution was cooled to about −55° C. toabout −70° C. and a solution of n-BuLi (1.6 M solution in hexane, 1.0equiv) was added over about 15 to about 20 minutes. The suspension wasstirred for about 15 to about 25 minutes at about −55° C. to about −60°C., followed by the slow addition of ZnCl₂ (0.5 M solution in THF, 1equiv). The suspension was stirred for about 30 minutes and warmed toambient temperature. To a separate flask was charged Compound (P-b) (1.0equiv) and Pd(PPh₃)₄ (231 mg, 4.4 mol %) in dioxane (about 20 vols). Themixture was degassed and transferred to the flask containing theorganozinc intermediate. The mixture was sealed and heated to about 115°C. to about 125° C. for about 15 hours then cooled to ambienttemperature. The reaction mixture was concentrated in vacuo at ambienttemperature and triturated with MTBE (about 10 mL) to afford Compound(C). ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (s, 1H), 7.51 (t, 1H, J=8.0 Hz),7.18 (d, 1H, J=4.0 Hz), 6.53 (d, 1H, J=8.0 Hz), 6.17 (s, 1H), 5.53 (sep,1H, J=8.0 Hz), 1.42 (d, 6H, J=8.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆):159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, for the metallation, in lieu ofn-BuLi, other organolithium reagents (such as t-BuLi, MeLi, and s-BuLi)or Grignard reagents (such as iPrMgCl and PhMgCl) may be used. In lieuof 1 equivalent of ZnCl₂, 0.5 equivalent of ZnCl₂ or ZnCl₂ with LiCl,ZnBr₂, or ZnI₂ can be used. Alternative solvents to THF can include2-MeTHF, MTBE, or Et₂O, and this reaction may take place at temperaturesthat range from about −78° C. to about −40° C.

Additionally, during the coupling reaction, alternative catalysts may beother Pd (II) complexes or Pd(0) complexes with trialkyl ortriarylphosphine ligands, such as Pd(PPh₃)₄. Various solvents, such asNMP, THF, butyronitrile, and toluene, may be employed. The reaction maytake place at temperatures that range from about 80° C. to about 140° C.

Example 5 Alternative Synthesis for Compound (D)

Carboalkoxylation to Form Compound (Q)

To a reaction flask was added 1-butanol (7 volumes). Compound (E) (1equiv) was added followed by K₂CO₃ (1.5 equiv) and Pd(dppf)Cl₂ (0.02equiv) and the reaction was placed under a CO atmosphere. The reactionmixture was heated at about 90° C. until reaction completion. Thereaction contents were cooled to ambient temperature, the reactionmixture was filtered through a pad of Celite to remove solids, and thenrinsed forward with EtOAc. The mother liquor was washed with water andbrine, and dried over Na₂SO₄, filtered, and concentrated to affordCompound (Q). Purification by flash chromatography afforded Compound(Q): ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=6.7 Hz, 1H), 7.39 (s, 1H),7.08 (d, J=10.8 Hz, 1H), 6.74 (s, 1H), 4.31 (t, J=6.6 Hz, 2H), 2.20 (s,3H), 1.87 (m, 1H), 1.73 (tt, J=6.7, 6.6 Hz, 3H), 1.43 (tq, J=7.3, 7.4Hz), 0.94 (t, J=7.4 Hz, 3H), 0.88 (m, 2H), 0.79 (m, 2H); Exact mass forCl₈H₂₂N₂O₂F [M+H], 317.2. Found [M+H], 317.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts may be used.Non-limiting examples include other Pd (II) complexes or Pd(0) complexeswith trialkyl or triarylphosphine ligands, such as PdCl₂(dppf) orPd(OAc)₂ with PPh₃, xantphos, tBu₃P—HBF₄, dppe, dppb, dpcb, tBu-dppf,and (Ad)₂P(nBu). Alternative bases can be used, such as other carbonatebases (such as Cs₂CO₃, and Na₂CO₃), NaOAc, KOAc, or organic bases suchas TMEDA, Et₃N, and iPr₂NEt. Various solvents may be employed, such as1-butanol with other co-solvents (e.g. DMF). The reaction may take placeat temperatures that range from about 70° C. to about 115° C. and at COpressures of about 5 to about 50 psig.

Hydrolysis of Compound (Q) to Compound (D)

To a reaction flask was added Compound (Q) (1.0 equiv) and MeOH (7volumes). A 25% NaOH solution (5 equiv) was then added dropwise.Consumption of Compound (D) was observed after about 1.5 hours at whichpoint the pH of the solution was carefully adjusted to about 1 by theaddition of 6 N HCl. Methanol was removed under vacuum to afford a solidwhich was isolated by filtration. The crude product was first trituratedin THF and then filtered. This solid was then triturated in CH₂Cl₂/MeOH(9:1) and filtered. Concentration of the mother liquor afforded Compound(D). ¹H NMR (400 MHz, CD₃OD) δ 8.87 (s, 1H), 7.94 (d, J=6.6 Hz, 1H),7.43 (s, 1H), 7.31 (d, J=11.5 Hz, 1H), 2.21 (s, 3H), 1.96 (m, 1H), 1.04(m, 2H), 0.81 (m, 2H); LRMS: Calculated mass for C₁₄H₁₄N₂O₂F [M+H],261.1. Found [M+H], 261.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, an alternative hydroxide base,including but not limited to KOH, LiOH, and CsOH, may be used in lieu ofNaOH. Various solvents may be employed, such as THF, EtOH, and2-propanol. The reaction may take place at temperatures that range fromabout 0° C. to about 50° C.

Example 6 Alternative Synthesis of Compound (A)

Compound (E) (1 equiv.), Compound (C) (1 equiv.), DMF (about 16 vols),Et₃N (1.5 equiv.), Pd(OAc)₂ (0.02 equiv.), and Ad₂P(n-Bu) (0.04 equiv.)were combined and the contents were purged with N₂ followed by CO andthen pressurized with CO (20 psi). The reaction mixture was heated toabout 95° C. to about 105° C.′ After about 24 hours, the reaction wasallowed to cool to about 20° C. to about 30° C. to afford Compound (A).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative catalysts may be used.Non-limiting examples include other Pd (II) complexes or Pd(0) complexeswith trialkyl or triarylphosphine ligands, such as PdCl₂(PPh₃)₂,PdCl₂(A-Phos)₂ or Pd(OAc)₂ with PPh₃. Alternative bases can be used,including but not limited to other organic bases (such as iPr₂NEt andTMEDA) and inorganic bases (such as NaOAc, KOAc, Na₂CO₃, and Cs₂CO₃).Various solvents, NMP, dioxane, and toluene, may be employed. Thereaction may take place at temperatures that range from about 90° C. toabout 120° C. and at CO pressures of about 20 psig to about 60 psig.

Example 7 Alternative Synthesis of Compound (A)

Compound (D) (1.0 equiv), Compound (C) (1.05 equiv),4-(dimethylamino)pyridine (1.0 equiv), ethyl acetate (about 4 V) anddiisopropylethylamine (1.2 equiv) were combined and the resulting slurrywas charged T3P® as a 50 wt % solution in ethyl acetate (2.0 equiv) overabout 3 min at about 20° C. During the addition, a small exotherm wasobserved. The mixture was stirred at about 20° C. for about 24 h. Afterreaction completion, 0.5 M aqueous hydrochloric acid (about 5 vols wasadded, and the mixture was stirred for about 15 min. Stirring was thenstopped, and the phases were allowed to separate. Then, the aqueousphase was reintroduced to the reactor. The pH of the aqueous solutionwas then adjusted to about 7 with a 5 wt % solution of aqueous sodiumhydroxide (about 12 vols). The resulting slurry was stirred for about 12h at about 20° C. and then filtered, and the reactor was rinsed forwardwith water (about 3 vols). The filter cake was washed with isopropanol(2 vols), and the resulting solids were dried under vacuum at about 45°C. to provide Compound (A).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of T3P®, other couplingreagents may be used, including but not limited to1,1′-carbonyldiimidazole, isobutyl chloroformate, pivoyl chloride,EDC-HCl/HOBt, thionyl chloride, and4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride.Alternative bases may be used, including but not limited organic amines(such as trialkyl amine bases (for example, triethylamine), N-methylmorpholine, and the like) and carbonates (such as lithium carbonates,sodium carbonates, cesium carbonates, and the like). Various solvents,such as DCM, THF, DMF, ethyl acetate, MTBE, toluene, NMP, DMAc,acetonitrile, dichloroethane, 2-MeTHF, and cyclopentyl methyl ether, maybe employed. The reaction may take place at temperatures that range fromabout −10° C. to about 60° C. or from about 0° C. to about 30° C.

Example 8 Alternative Synthesis of Compound (C)

The mixture of Compound (8-a) and Compound (8-b) is dissolved in about10 volumes of process water. The solution is heated to about 80° C., andthe solution is allowed to age for about 6 hours. Upon reactioncompletion, the solution is cooled to about 60° C. The reaction mixtureis seeded with 0.001 equiv of Compound (C), which was obtained bysuitable means, and cooled to about 0° C. Compound (C) is filtered fromthe cold aqueous solution to yield the product.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, instead of the mixture of Compound(8-a) and (8-b), the reaction may be carried out with Compound (8-a) orCompound (8-b). Additionally, other organic acids may be used, includingbut not limited to acetic acid and trifluoroacetic acid. Varioussolvents, such as toluene, dimethylacetamide, NMP, and 2-MeTHF, may beemployed. The reaction may take place at temperatures that range fromabout 80° C. to about 110° C. or about 100° C.

Example 9 Alternative Synthesis of Compound (C)

Compound (C) may be synthesized as described in U.S. Pat. No. 8,742,126,which is hereby incorporated by reference in its entirety. Additionally,when starting with Compound (9-a), it was found that Compound (C) may beformed through two additional intermediates, Compound (9-b) and Compound(9-c). LRMS for Compound (9-b): Calculated mass, C₁₄H₁₄N₂O₂F[M+H],235.1. Found [M+H], 235.9. LRMS for Compound (9-c): Calculated mass,C₁₄H₁₄N₂O₂F [M+H], 207.1. Found [M+H], 208.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, in lieu of acetic acid, other organicacids may be used, including but not limited to trifluoroacetic acid.Various solvents, such as toluene, dimethylacetamide, NMP, 2-MeTHF,acetic acid, and water, may be employed. The reaction may take place attemperatures that range from about 80° C. to about 110° C. or about 100°C.

Example 10 Alternative Synthesis of Compound (C)

Compound (10-a) (1 equiv), toluene (about 20 vols), N-isopropylformamide(3.00 equiv), isopropylamine (3.00 equiv) and trifluoroacetic acid (2.50equiv) were sequentially combined. The vial was sealed and heated toabout 100° C. After about 22 h, the vial was cooled to room temperatureand the contents were analyzed by HPLC. Compound (C) was observed byHPLC.

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, other organic acids may be used,including but not limited to acetic acid. Various solvents, such asdimethylacetamide, NMP, and acetic acid, may be employed. The reactionmay take place at temperatures that range from about 80° C. to about110° C. or about 100° C.

Example 11 Alternative Synthesis of Compound (C)

Compound (10-a) (1.0 equiv), toluene (about 12 volumes), 79 wt %(E)-N′-isopropyl-N,N-dimethylformimidamide (3.0 equiv), isopropylamine(3.0 equiv) and trifluoroacetic acid 2.5 equiv) were combined and heatedto about 100° C. After about 22 h, the reaction mixture was cooled toroom temperature. The mixture was seeded with Compound (C), which wasobtained by suitable means, and cooled to about 0° C. After about 30min, the heterogeneous mixture was filtered and the vial was rinsedforward with toluene (about 25 vols). The solid was collected and driedunder vacuum at about 40° C. to provide Compound (C).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, organic acids may be used, includingbut not limited to acetic acid. Various solvents, such as acetic acid,dimethylacetamide, and NMP, may be employed. Alternative organic aminesmay also be added. The reaction may take place at temperatures thatrange from about 80° C. to about 110° C. or about 90° C. to about 100°C.

Example 12 Alternative Synthesis of Compound (C)

A suitable reactor fitted with a reflux condenser was charged with acylhydrazide (1 equiv), toluene (6 volumes), isopropylamine (7.20 equiv)and N,N-dimethylformamide dipropyl acetal (2.70 equiv). To the resultingslurry was charged acetic acid (1.50 equiv) over about 2 min at about20° C. During the addition, an exotherm was observed. The mixture washeated to about 95° C. for about 20 h. After reaction completion, themixture was concentrated under vacuum at about 80° C. The mixture wasdiluted with water (10 volumes), and the resulting biphasic solution wasconcentrated under vacuum at about 80° C. Water was added (3 volumes),and the solution is heated to about 85° C. The resulting solution wascooled to about 60° C. and seeded with Compound (C), which was obtainedby suitable means. The resulting slurry was aged for about 30 min andthen cooled to about 20° C. over about 1 h and aged for about 15 h. Theresulting slurry was cooled to about 5° C. and aged for about 3 h. Thecold slurry is filtered and the reactor is rinsed forward with coldwater (15 mL). The resulting solids were dried under vacuum at about 40°C. to give Compound (C).

Alternative reagents and reaction conditions to those disclosed abovemay also be employed. For example, alternative formamide reagents may beused, such as dimethyl formamide diethyl acetal, dimethyl formamidediisopropyl acetal, dimethyl formamide disec-butyl acetal, dimethylformamide diisobutyl acetal, and the like. Other organic acids may beused, including but not limited to trifluoroacetic acid, chloroaceticacid, and methanesulfonic acid. Various solvents, such as acetic acid,dimethylacetamide, 2-MeTHF, NMP, isobutyl acetate, isobutanol, water,and isopropyl acetate, may be employed. The reaction may take place attemperatures that range from about 75° C. to about 110° C. or about 100°C.

Example 13 Forms of Compound (D)

Crystalline forms of Compound (D), and salts and hydrates thereof, wereanalyzed by XRPD, DSC and TGA. XRPD patterns were collected with aPANalytical X'Pert PRO MPD diffractometer using mostly the followingexperimental setting: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 2-40° 2θ,step size 0.0167° 2θ. The DSC analysis was conducted on a TA InstrumentsQ2000 differential scanning calorimeter using about 2 to about 3 mg ofmaterial, 10° C./min heating rate over the range of (−30° C.)-300° C.The TGA data were obtained on TA Instruments 2950 and Q5000thermogravimetric analyzers using about 2 to about 5 mg of material, 10°C./min heating rate over the range of 25-350° C.

1.1 Compound of Formula (D-a) Form I

Compound of Formula (D-a) Form I is prepared as described in Example 1and is an anhydrous crystalline form obtained from MeOH/MTBE (1:4)solvent system. Compound of Formula (D-a) Form I was characterized byXRPD, DSC and TGA. XRPD pattern is presented in FIG. 1. TGA did not showany weight loss below about 150° C., about 6% weight loss was observedat about 150 to about 200° C., and about 6.4% weight loss at about 200to about 240° C., followed by decomposition (FIG. 3). This weight losscould correspond to the loss of HCl (1 equivalent HCl=12.3%). DSCthermogram showed possible endotherm with onset at about 210° C. (FIG.2). Compound of Formula (D-a) Form I is a kinetic form, which eventuallyconverts to thermodynamically more stable Compound of Formula (D-a) FormII after the slurry equilibration.

1.2 Compound of Formula (D-a) Form II

Compound of Formula (D-a) Form II is prepared as described in Example 1and is an anhydrous crystalline form obtained from MeOH/MTBE (1:4)solvent mixture after about 15 hrs equilibration. Compound of Formula(D-a) Form II was characterized by XRPD, DSC and TGA. XRPD pattern ispresented in FIG. 4. TGA did not show any weight loss below about 150°C., about 7.5% weight loss was observed at about 150 to about 190° C.and about 8.2% weight loss at about 190 to about 220° C. most likelycorresponding to the loss of HCl (slightly more than 1 equivalent),followed by decomposition (FIG. 6). DSC thermogram showed possibleendotherm with onset at about 217° C. (FIG. 5). Compound of Formula(D-a) Form II is a thermodynamically more stable form than Compound ofFormula (D-a) Form I, which was confirmed by competitive slurryexperiments in MeOH and in MeOH/MTBE (1:4) at room temperature.

2.1 Compound of Formula (D) Hydrate Form I

Compound of Formula (D) hydrate Form I was isolated from the currentprocess Compound of Formula (D) zwitterion and was obtained by pHadjustment to pH about 5 in water. Initial characterization of Compoundof Formula (D) hydrate Form I was performed using XRPD, DSC, TGA and KF.XRPD pattern was crystalline with some preferred orientation (FIG. 7).TGA showed about 4.0% step weight loss at about 50 to about 110° C.(FIG. 9). DSC showed broad endotherm with onset at about 89° C.corresponding to the solvent loss, followed by sharp endotherm withonset at about 252° C. (FIG. 8). KF analysis showed about 3.3% water,which corresponds to about 0.5 equivalents of water. This material wasdesignated as Compound of Formula (D) hydrate Form I.

A stable form screen of Compound of Formula (D) hydrate Form I wasperformed in an attempt to determine the stability of Compound ofFormula (D) hydrate Form I in different organic solvents. Table 1summarizes the experimental details and results. Compound of Formula (D)hydrate Form I (about 50 to about 60 mg) was slurried in about 1 mL ofchosen solvent. Solids were analyzed by XRPD after about 1 day and about2 weeks of equilibration at room temperature. After about 1 day ofstirring, all water miscible solvents (MeCN, MeOH, EtOH, IPA, acetone,and THF) afforded Form I. Solids in DCM were consistent with Compound ofFormula (D) hydrate Form I. XRPD patterns of the solids from 2-MeTHF,EtOAc, and IPAc showed a mixture of Compound of Formula (D) Form I andCompound of Formula (D) hydrate Form I. After about 2 weeks ofequilibration, Compound of Formula (D) Form I was also obtained in EtOAcand IPAc in addition to previously mentioned solvents. No from changewas observed in DCM. A mixture of Compound of Formula (D) Form I andCompound of Formula (D) hydrate Form I was still observed in 2-MeTHF.These data suggest that hydrated form (Compound of Formula (D) hydrateForm I) could be easily converted to an anhydrous form (Compound ofFormula (D) Form I) in water miscible solvents.

2.2 Hydrate Screen of Compound of Formula (D) Form I and of Compound ofFormula (D) Form II

A hydrate screen of Compound of Formula (D) was performed using amixture of anhydrous forms of Compound of Formula (D) Form II and ofCompound of Formula (D) Form I and EtOH/water solvent mixtures withdifferent water activities (Table 1). Compound of Formula (D) Form IIand Compound of Formula (D) Form I (about 20 to about 40 mg) wasslurried in about 1 mL of EtOH/water or water. Samples were analyzedafter about 1 day and after about 2 weeks of equilibration at roomtemperature. Pure anhydrous Compound of Formula (D) Form I was obtainedafter 1 day in mixtures with about 0.2 to about 0.4 water activity.However, after 2 weeks of equilibration a new form was obtained inEtOH/water with 0.4 water activity. This form was designated as Compoundof Formula (D) Form III. Compound of Formula (D) hydrate Form I wasobtained in solvents with about 0.5 to about 1.0 water activity after 1day and after about 2 weeks.

TABLE 1 Hydrate screen of Compound of Formula (D) Form II and Compoundof Formula (D) Form I. Water activity in water EtOH EtOH/ amount amountXRPD after 1 Solubility XRPD after 2 water (mL) (mL) day (wet) (mg/mL)weeks (wet) 0.2 0.031 0.969 Form I 7.27 Form I 0.3 0.066 0.934 Form I8.06 Form I 0.4 0.077 0.923 Form I 7.86 Form III 0.5 0.097 0.903 HydrateForm I 8.16 Hydrate Form I 0.6 0.149 0.851 Hydrate Form I 6.59 HydrateForm I 0.7 0.263 0.737 Hydrate Form I 6.88 Hydrate Form I 0.8 0.4810.519 Hydrate Form I 6.56 Hydrate Form I 0.9 0.825 0.175 Hydrate Form I3.93 Hydrate Form I 1.0 1.0 0 Hydrate Form I 3.32 Hydrate Form I

2.3 Stable Form Screen of Compound of Formula (D) Hydrate Form I

A stable form screen of Compound of Formula (D) hydrate Form I wasperformed in an attempt to determine the stability of Compound ofFormula (D) hydrate Form I in different organic solvents. Table 2summarizes the experimental details and results. Compound of Formula (D)hydrate Form I (about 50 to about 60 mg) was slurried in 1 mL of chosensolvent. Solids were analyzed by XRPD after 1 day and 2 weeks ofequilibration at room temperature. After 1 day of stirring, all watermiscible solvents (MeCN, MeOH, EtOH, IPA, acetone, and THF) affordedCompound of Formula (D) Form I. Solids in DCM were consistent withCompound of Formula (D) hydrate Form I. XRPD patterns of the solids from2-MeTHF, EtOAc, and IPAc showed a mixture of Compound of Formula (D)Form I and Compound of Formula (D) hydrate Form I. After about 2 weeksof equilibration, Compound of Formula (D) Form I was also obtained inEtOAc and IPAc in addition to previously mentioned solvents. No formchange was observed in DCM. A mixture of Compound of Formula (D) Form Iand Compound of Formula (D) hydrate Form I was still observed in2-MeTHF. These data suggest that hydrated form (Compound of Formula (D)hydrate Form I) could be easily converted to an anhydrous form (Compoundof Formula (D) Form I) in water miscible solvents.

TABLE 2 Stable form screen of Compound of Formula (D) Hydrate Form I.XRPD in 1 day Solubility Solvent (wet) (mg/mL) XRPD in 2 weeks MeCN FormI 0.40 Form I MeOH Form I 20.67 Form I EtOH Form I 6.18 Form I IPA FormI 2.90 Form I Acetone Form I 1.99 Form I DCM Hydrate 0.19 Hydrate THFForm I 11.79 Form I 2- Form I + Hydrate 4.48 Form I + Hydrate MeTHFEtOAc Form I + 0.73 Form I 1 peak of Hydrate IPAc Form I + Hydrate 0.45Form I

2.4 Competitive Slurries of Compound of Formula (D) Form III and Form I

Three anhydrous forms of Compound of Formula (D) were observed to date:Compound of Formula (D) Form I, Compound of Formula (D) Form II, andCompound of Formula (D) Form III. Compound of Formula (D) Form II wasfound to be a less stable form than and Compound of Formula (D) Form I.Compound of Formula (D) Form II converted to Compound of Formula (D)Form I in EtOH/water with about 0.2 to about 0.4 water activity as wasdiscussed above.

Compound of Formula (D) Form I, however, converted to another anhydrousform—Compound of Formula (D) Form III—in EtOH/water with 0.4 wateractivity after 2 weeks of equilibration. In an attempt to confirm thestability of Compound of Formula (D) Form I and Compound of Formula (D)Form III, a competitive slurry experiment was conducted using acetone asa solvent. The solids were analyzed by XRPD after 1 day and 8 days ofstirring at room temperature. A mixture of forms Compound of Formula (D)Form I and Compound of Formula (D) Form III was observed after 1 day.However, full conversion of Compound of Formula (D) Form I to Compoundof Formula (D) Form III was observed after 8 days suggesting thatCompound of Formula (D) Form III is thermodynamically more stable formthan Compound of Formula (D) Form I.

2.5 Compound of Formula (D) Form I

Compound of Formula (D) Form I was obtained after the isothermal hold ofCompound of Formula (D) hydrate Form I at about 150° C. XRPD pattern ispresented in FIG. 10. Compound of Formula (D) Form I was also obtainedafter KF analysis of Compound of Formula (D) Form II and Compound ofFormula (D) Form I at about 180° C. Slurries of Compound of Formula (D)hydrate Form I in water miscible organic solvents also afforded Compoundof Formula (D) Form I (MeCN, MeOH, EtOH, IPA, acetone, and THF). TGAshowed about 0.2% continuous weight loss below about 150° C. (FIG. 10).DSC thermogram afforded single endotherm with onset at about 252° C.(FIG. 11). DVS analysis showed that Form I is slightly hygroscopic withonly about 0.5% moisture uptake at 90% RH. No form change was observedafter DVS.

Compound of Formula (D) Form I is a stable anhydrous form and is morestable than Compound of Formula (D) Form II. However, competitiveslurries with Compound of Formula (D) Form III showed that Compound ofFormula (D) Form I is less stable than Compound of Formula (D) Form III.Form I converts to Compound of Formula (D) hydrate Form I in EtOH/waterat 0.5-1.0 water activity.

2.6 Compound of Formula (D) Form I and Compound of Formula (D) Form II

Compound of Formula (D) Form II was obtained in a mixture with Compoundof Formula (D) Form I after vacuum drying at about 70° C. of Compound ofFormula (D) hydrate Form I. XRPD pattern is presented in FIG. 18. Thefollowing characteristic peaks of compound of Formula (D) Form II weredetected by subtraction of peaks of compound of Formula (D) Form I fromthe mixture: 5.2, 8.4, 9.8, 10.4, 13.2, 13.6, 14.4, 15.5, 19.5, 25.0,25.4, and 27.5 °2θ±0.2 °2θ. TGA showed about 0.2% continuous weight lossbelow about 150° C. (FIG. 16). DSC thermogram afforded small endothermwith onset at about 131° C. most likely corresponded to the formconversion, and sharp endotherm with onset at about 252° C. (FIG. 17).KF analysis of Compound of Formula (D) Form H and Compound of Formula(D) I at about 110° C. showed 0% water. No form conversion was observedafter KF at 110° C. KF analysis at about 180° C. showed 0.08% water.XRPD pattern of the solids after KF at 180° C. was consistent withCompound of Formula (D) Form I.

Compound of Formula (D) Form II is a less stable anhydrous form thanCompound of Formula (D) Form I. Compound of Formula (D) Form II fullyconverts to Compound of Formula (D) Form I after heating to >150° C.,and after the slurry in EtOH/water at 0.2-0.4 water activity. Compoundof Formula (D) Form II converts to Compound of Formula (D) hydrate FormI in EtOH/water at 0.5-1.0 water activity.

2.7 Compound of Formula (D) Form III

Compound of Formula (D) Form III was obtained from EtOH/water (0.4 wateractivity) mixture after 2 weeks slurry of Compound of Formula (D) FormII and Compound of Formula (D) Form I. XRPD pattern of Form III ispresented in FIG. 13. TGA shows about 0.3% continuous weight loss belowabout 150° C. (FIG. 15). DSC thermogram afforded endotherm with onset atabout 164° C. most likely corresponded to the form conversion, and sharpendotherm with onset at about 253° C. (FIG. 14). KF at about 110° C.showed 0% water and no form conversion. KF at about 200° C. showed 0.27%water and afforded solids with XRPD pattern consistent with Compound ofFormula (D) Form I.

However, Compound of Formula (D) Form III was found to be more stablethan Compound of Formula (D) Form I based on competitive slurries ofCompound of Formula (D) Form I and Compound of Formula (D) Form III inacetone. Full conversion of Compound of Formula (D) Form I to Compoundof Formula (D) Form III was observed after 8 days of slurry at RT.Slurry experiment showed that Compound of Formula (D) Form III convertedto Compound of Formula (D) hydrate Form I in EtOH/water (0.9 wateractivity) overnight.

2.8 Drying Study of Compound of Formula (D) Hydrate Form I

Based on XRPD data, form conversion was observed for Compound of Formula(D) hydrate Form I after KF analysis at 110° C. The TGA drying study wasperformed as summarized in Table 3. The sample of Compound of Formula(D) hydrate Form I was heated up to 150° C. at 10° C./min and was heldat this temperature for 10 min, followed by cooling to RT and XRPDanalysis. XRPD pattern of this material was mostly consistent with XRPDpattern of the solids obtained after KF of hydrate Form I (at 0.110° C.)with some missing peaks, and it was designated as Compound of Formula(D) Form I.

In an attempt to scale up Compound of Formula (D) Form I, Compound ofFormula (D) hydrate Form I was dried under vacuum at 70° C. for 3 days(over weekend). XRPD pattern afforded a mixture of Compound of Formula(D) Form I and Compound of Formula (D) Form II.

TABLE 3 TGA drying study of Compound of Formula (D) Hydrate Form I.Method Results 1) Heat to 150° C. at 10° C./min and 1) 3.9% weight loss;hold at 150° C. for 10 min; 2) New form by XRPD - 2) XRPD Compound ofFormula (D) Form I

The present disclosure is not to be limited in scope by the specificembodiments disclosed in the examples, which are intended to beillustrations of a few embodiments of the disclosure, nor is thedisclosure to be limited by any embodiments that are functionallyequivalent within the scope of this disclosure. Indeed, variousmodifications of the disclosure in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. To this end, it shouldbe noted that one or more hydrogen atoms or methyl groups can be omittedfrom the drawn structures consistent with accepted shorthand notation ofsuch organic compounds, and that one skilled in the art of organicchemistry would readily appreciate their presence.

What is claimed is:
 1. Crystalline5-(4-cyclopropyl-1H-imidazol-1-1-2-fluoro-4-methylbenzoic acidhydrochloride (Compound of formula (D-a) Form I) characterized by anX-ray powder diffractogram comprising the following peaks: 7.3, 22.3,23.4, 23.9, and 26.8 °2θ±0.2 °2θ, as determined on a diffractometerusing Cu—Kα radiation at a wavelength of 1.5406 Å.
 2. Compound offormula (D-a) Form I according to claim 1, wherein the diffractogramfurther comprises peaks at 11.5, 13.4, 20.9, and 22.0 °2θ±0.2 °2θ. 3.Compound of formula (D-a) Form I according to claim 1, wherein thediffractogram is substantially as shown in FIG.
 1. 4. Compound offormula (D-a) Form I according to claim 1, characterized by adifferential scanning calorimetry (DSC) curve that comprises anendotherm at about 210° C.
 5. Compound of formula (D-a) Form I accordingto claim 4, wherein the DSC curve is substantially as shown in FIG. 2.